Drug coated balloon catheters for nonvascular strictures

ABSTRACT

Embodiments of the present invention provide a method of treating a stricture in a nonvascular body lumen such as urethral strictures, benign prostatic hyperplasia (BPH) strictures, ureteral strictures, esophageal strictures, sinus strictures, and biliary tract strictures. Embodiments of the present invention provide a method for treating at least one of benign prostatic hyperplasia (BPH), prostate cancer, asthma, and chronic obstructive pulmonary disease (COPD). The method can include delivering, for example, via drug coated balloon catheters, anti-inflammatory and anti-proliferative drugs (e.g., rapamycin, paclitaxel, and their analogues) and one or more additives.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. patent application Ser. No.17/951,321, filed Sep. 23, 2022, which is a a continuation of U.S.patent application Ser. No. 17/107,136, filed Nov. 30, 2020, which is aa continuation of U.S. patent application Ser. No. 15/568,614, filedOct. 23, 2017, which is a U.S. National Stage Application under 35U.S.C. 371 from International Application No. PCT/US2016/028652, filedApr. 21, 2016, which claims the benefit of priority to U.S. ProvisionalPatent Application Ser. No. 62/152,559 filed Apr. 24, 2015, thedisclosures of which are incorporated herein in their entirety byreference.

BACKGROUND

Benign prostatic hyperplasia is a non-cancerous enlargement of theprostate gland, affecting more than 50% percent of men over the age of60. The prostate early in life is the size and shape of a walnut andweight about 20 grams. Prostate enlargement appears to be a normalprocess. With age, the prostate gradually increases in size to twice ormore its normal size. As the prostate grows, it presses against andnarrows the urethra, causing a urinary obstruction that makes itdifficult to urinate.

Male urethral stricture disease occurred at a rate as high as 0.6% insome populations. Urethral stricture diseases appeared to be more commonin the elderly population. The patients with the strictures experiencemoderate complications, such as bother from lower urinary tract voidingsymptoms, recurrent urinary tract infection and the need for repeaturethral procedures such as dilation or urethrotomy.

Ureteral strictures of upper urinary tract are either congenital oracquired. Congenital ureteral strictures are most commonly located atthe ureteropelvic junction. Most of ureteral strictures are acquired andusually are iatrogenic. The most common etiology of the ureteralstrictures is injury during endoscopic, open, or laparoscopic surgicalprocedures.

Esophageal strictures are a problem commonly encountered ingastroenterological medicine and can be caused by malignant or benignlesions. Dysphagia is the symptom experienced by all patients. Most ofthese patients require palliative treatment to relieve the dysphagia.

Chronic obstructive pulmonary disease (COPD) is a term used to classifytwo major airflow obstruction disorders: chronic bronchitis andemphysema. Approximately 16 million Americans have COPD, 80-90% of themwere smokers throughout much of their lives. COPD is a leading cause ofdeath in the U.S. Chronic bronchitis is inflammation of the bronchialairways. The bronchial airways connect the trachea with the lungs. Wheninflamed, the bronchial tubes secrete mucus, causing a chronic cough.Emphysema is an overinflation of the alveoli, or air sacs in the lungs.This condition causes shortness of breath.

Asthma is a chronic respiratory disease characterized by inflammation ofthe airways, excess mucus production and airway hyper responsiveness,and a condition in which airways narrow excessively or too easilyrespond to a stimulus. Asthma episodes or attacks cause narrowing of theairways, which make breathing difficult. Asthma attacks can have asignificant impact on a patient's life, limiting participation in manyactivities. In severe cases, asthma attacks can be life threatening.Presently, there is no known cure for asthma.

Chronic sinusitis is an inflammation of the membrane lining of one ormore paranasal sinuses. Chronic sinusitis lasts longer than three weeksand often continues for months. In cases of chronic sinusitis, there isusually tissue damage. According to the Center for Disease Control(CDC), thirty seven million cases of chronic sinusitis are reportedannually.

SUMMARY OF THE INVENTION

One aspect of the invention is to deliver paclitaxel, rapamycin, ortheir analogues, to the wall of a body lumen to treat the narrowing orstricture.

The antimicrobial properties of various fatty acids and monoglyceridesof C8-C12 fatty acids have been investigated for many years. The studieshave confirmed that both fatty acids and monoglycerides are capable ofinhibiting the growth of numerous types of bacteria and viruses. In oneembodiment, the coating formulation includes various fatty acids andmonoglycerides of C8-C12 fatty acids, such as caprylic acid,monocaprilin, capric acid, monocaprin, lauric acid and monolaurin, asone of the additives for the treatment of various diseases.

The causes of nonvascular diseases of benign prostatic hyperplasia (BPH)strictures, urethral strictures, ureteral strictures, prostate cancer,esophageal strictures, biliary tract strictures, asthma and chronicobstructive pulmonary disease (COPD) are infections and inflammations bybacteria and viruses. It is beneficial to have a coating formulation ofdrugs and additives which have the properties of killing and inhibitionof the bacteria and viruses.

The present invention provides new methods for treatments of nonvasculardiseases of benign prostatic hyperplasia (BPH) strictures, urethralstrictures, ureteral strictures, prostate cancer, esophageal strictures,biliary tract strictures, asthma and chronic obstructive pulmonarydisease (COPD) to have a long term and persistent effect. The newmethods will prevent renarrowing and recurrent strictures. The methodsinvolve delivering of anti-inflammatory and anti-proliferate drugs(e.g., rapamycin, paclitaxel, or their analogues) and one or morewater-soluble additives to a target tissue. Embodiments of the presentinvention provide a medical device coating formulation including a drugfor treatment of the strictures in nonvascular body lumens, andadditives that enhance absorption of the drug into tissue of body lumensand have a property of antibacterial and viruses.

Embodiments of the present disclosure are directed to the treatment ofstrictures in nonvascular body lumens by delivering of an effectiveamount of anti-inflammatory and anti-proliferate drugs (e.g., rapamycin,paclitaxel, or their analogues) to a target tissue. The strictures innonvascular body lumens include urethral strictures, ureteralstrictures, esophageal strictures, sinus strictures, and biliary tractstrictures. Embodiments of the present disclosure are directed tomethods for treating at least one of benign prostatic hyperplasia (BPH),narrowing urethral, prostate cancer, asthma, and chronic obstructivepulmonary disease (COPD). The treatment is intended for a variety ofanimals, such as premature neonates to adult humans.

By coating the exterior surface of a medical device, and particularly ofa balloon catheter or a stent, for example, with a layer including atherapeutic agent and additives that have a hydrophilic part and a drugaffinity part, it is useful in solving the problems associated with thecoatings discussed above. The drug affinity part is a hydrophobic partand/or has an affinity to the therapeutic agent by hydrogen bondingand/or van der Waals interactions. Surprisingly, additives according toembodiments of the present invention, which include a hydrophilic partand a drug affinity part, in combination with a therapeutic agent, formsan effective drug delivery coating on a medical device without the useof oils and lipids, thereby avoiding the lipolysis dependence and otherdisadvantages of conventional oil-based coating formulations. Moreover,the additives according to embodiments of the present inventionfacilitate rapid drug elution and superior permeation of drug intotissues at a disease site. Thus, coatings according to embodiments ofthe present invention provide an enhanced rate and/or extent ofabsorption of the hydrophobic therapeutic agent in nonvascular diseasedtissues or nonvascular body lumens. In embodiments of the presentinvention, the coated device delivers therapeutic agent to nonvasculartissues during a very brief deployment time of less than 10 minutes,less than 2 minutes, and reduces renarrowing and reoccurring of thestrictures of a nonvascular body lumen.

In one embodiment, the present invention relates to a medical device fordelivering a therapeutic agent to a nonvascular tissue or nonvascularbody lumen, the device including a layer overlying an exterior surfaceof the medical device. The device includes one of a balloon catheter, aperfusion balloon catheter, an infusion catheter such as distalperforated drug infusion tube, a perforated balloon, spaced doubleballoon, porous balloon, and weeping balloon, a cutting ballooncatheter, a scoring balloon catheter. Further, the nonvascular tissueincludes tissue of one of esophagus, airways, sinus, trachea, colon,biliary tract, urinary tract, prostate, urethral, ureteral, and othernonvascular lumens. The balloon catheters have a polyether-amide blockcopolymers as shafts and balloon materials.

In one embodiment of the medical devices, the additive enhancesabsorption of the drug into nonvascular tissue of the body lumens. Thenonvascular body lumens include esophagus, airways, sinus, trachea,colon, biliary tract, urinary tract, prostate, urethral, ureteral, andother nonvascular lumens. In another embodiment of the medical devices,the additive includes a hydrophilic part and a drug affinity part,wherein the drug affinity part is at least one of a hydrophobic part, apart that has an affinity to the therapeutic agent by hydrogen bonding,and a part that has an affinity to the therapeutic agent by van derWaals interactions. In one embodiment, the drug is not enclosed inmicelles or encapsulated in polymer particles.

In one embodiment of the medical devices, the additive is at least oneof a surfactant and a chemical compound. In one embodiment, the chemicalcompound is chosen from amino alcohols, hydroxyl carboxylic acid, ester,anhydrides, hydroxyl ketone, hydroxyl lactone, hydroxyl ester, sugarphosphate, sugar sulfate, ethyl oxide, ethyl glycols, amino acids,peptides, proteins, sorbitan, glycerol, polyalcohol, phosphates,sulfates, organic acids, esters, salts, vitamins, combinations of aminoalcohol and organic acid, and their substituted molecules. In oneembodiment, the surfactant is chosen from ionic, nonionic, aliphatic,and aromatic surfactants, PEG fatty esters, PEG omega-3 fatty esters,ether, and alcohols, glycerol fatty esters, sorbitan fatty esters, PEGglyceryl fatty esters, PEG sorbitan fatty esters, sugar fatty esters,PEG sugar esters, and derivatives thereof. In another embodiment, thechemical compound has one or more hydroxyl, amino, carbonyl, carboxyl,acid, amide or ester groups. In another embodiment, the chemicalcompound having one or more hydroxyl, amino, carbonyl, carboxyl, acid,amide or ester groups is chosen from amino alcohols, hydroxyl carboxylicacid, ester, anhydrides, hydroxyl ketone, hydroxyl lactone, hydroxylester, sugar phosphate, sugar sulfate, ethyl oxide, ethyl glycols, aminoacids, peptides, proteins, sorbitan, glycerol, polyalcohol, phosphates,sulfates, organic acids, esters, salts, vitamins, combinations of aminoalcohol and organic acid, and their substituted molecules.

In one embodiment of the medical devices, a coating layer overlying theexterior of the medical device includes one or more water-solubleadditives. In one embodiment, the water-soluble additive is chosen fromp-isononylphenoxypolyglycidol, PEG laurate, Tween 20, Tween 40, Tween60, Tween 80, PEG oleate, PEG stearate, PEG glyceryl laurate, PEGglyceryl oleate, PEG glyceryl stearate, polyglyceryl laurate,plyglyceryl oleate, polyglyceryl myristate, polyglyceryl palmitate,polyglyceryl-6 laurate, plyglyceryl-6 oleate, polyglyceryl-6 myristate,polyglyceryl-6 palmitate, polyglyceryl-10 laurate, plyglyceryl-10oleate, polyglyceryl-10 myristate, polyglyceryl-10 palmitate, PEGsorbitan monolaurate, PEG sorbitan monolaurate, PEG sorbitan monooleate,PEG sorbitan stearate, PEG oleyl ether, PEG laurayl ether, octoxynol,monoxynol, tyloxapol, sucrose monopalmitate, sucrose monolaurate,decanoyl-N-methylglucamide, n-decyl-β-D-glucopyranoside,n-decyl-β-D-maltopyranoside, n-dodecyl-β-D-glucopyranoside,n-dodecyl-β-D-maltoside, heptanoyl-N-methylglucamide,n-heptyl-β-D-glucopyranoside, n-heptyl-β-D-thioglucoside,n-hexyl-β-D-glucopyranoside, nonanoyl-N-methylglucamide,n-nonyl-β-D-glucopyranoside, octanoyl-N-methylglucamide,n-octyl-O-D-glucopyranoside, octyl-β-D-thioglucopyranoside; cystine,tyrosine, tryptophan, leucine, isoleucine, phenylalanine, asparagine,aspartic acid, glutamic acid, and methionine; acetic anhydride, benzoicanhydride, ascorbic acid, 2-pyrrolidone-5-carboxylic acid, sodiumpyrrolidone carboxylate, ethylenediaminetetraacetic dianhydride, maleicand anhydride, succinic anhydride, diglycolic anhydride, glutaricanhydride, acetiamine, benfotiamine, pantothenic acid, cetotiamine,cycothiamine, dexpanthenol, niacinamide, nicotinic acid, pyridoxal5-phosphate, nicotinamide ascorbate, riboflavin, riboflavin phosphate,thiamine, folic acid, menadiol diphosphate, menadione sodium bisulfite,menadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin K6, and vitaminU; albumin, immunoglobulins, caseins, hemoglobins, lysozymes,immunoglobins, a-2-macroglobulin, fibronectins, vitronectins,firbinogens, lipases, benzalkonium chloride, benzethonium chloride,docecyl trimethyl ammonium bromide, sodium docecylsulfates, dialkylmethylbenzyl ammonium chloride, and dialkylesters of sodiumsulfonsuccinic acid, L-ascorbic acid and its salt, D-glucoascorbic acidand its salt, tromethamine, triethanolamine, diethanolamine, meglumine,glucamine, amine alcohols, glucoheptonic acid, glucomic acid, hydroxylketone, hydroxyl lactone, gluconolactone, glucoheptonolactone,glucooctanoic lactone, gulonic acid lactone, mannoic lactone, ribonicacid lactone, lactobionic acid, glucosamine, glutamic acid, benzylalcohol, benzoic acid, hydroxybenzoic acid, propyl 4-hydroxybenzoate,lysine acetate salt, gentisic acid, lactobionic acid, lactitol, sinapicacid, vanillic acid, vanillin, methyl paraben, propyl paraben, sorbitol,xylitol, cyclodextrin, (2-hydroxypropyl)-cyclodextrin, acetaminophen,ibuprofen, retinoic acid, lysine acetate, gentisic acid, catechin,catechin gallate, tiletamine, ketamine, propofol, lactic acids, aceticacid, salts of any organic acid and organic amine, polyglycidol,glycerol, multiglycerols, galactitol, di(ethylene glycol), tri(ethyleneglycol), tetra(ethylene glycol), penta(ethylene glycol), poly(ethyleneglycol) oligomers, di(propylene glycol), tri(propylene glycol),tetra(propylene glycol, and penta(propylene glycol), poly(propyleneglycol) oligomers, a block copolymer of polyethylene glycol andpolypropylene glycol, creatine, creatinine, agmatine, citrulline,guanidine, sucralose, aspartame, hypoxanthine, theobromine,theophylline, adenine, uracil, uridine, guanine, thymine, thymidine,xanthine, xanthosine, xanthosine monophosphate, caffeine, allantoin,(2-hydroxyethyl)urea, N,N′-bis(hydroxymethyl)urea, pentaerythritolethoxylate, pentaerythritol propoxylate, pentaerythritolpropoxylate/ethoxylate, glycerol ethoxylate, glycerol propoxylate,trimethylolpropane ethoxylate, pentaerythritol, dipentaerythritol, crownether, 18-crown-6, 15-crown-5, 12-crown-4, N-acetylglucosamine,N-octyl-D-gluconamide, C6-ceramide, dihydro-C6-ceramide, cerabroside,sphingomyelin, galaclocerebrosides, lactocerebrosides,N-acetyl-D-sphingosine, N-hexanoyl-D-sphingosine,N-octonoyl-D-sphingosine, N-Lauroyl-D-sphingosine,N-palmitoyl-D-sphingosine, N-oleoyl-D-sphingosine, PEG caprylic/capricdiglycerides, PEG8 caprylic/capric glycerides, PEG caprylate, PEG8caprylate (e.g., Labrasol®), PEG caprate, PEG caproate, glycerylmonocaprylate, glyceryl monocaprate, glyceryl monocaproate, monolaurin,monocaprin, monocaprylin, monomyristin, monopalmitolein, monoolein,derivatives thereof, and combinations thereof.

In one embodiment, the one or more water-soluble additives are chosenfrom N-acetylglucosamine, N-octyl-D-gluconamide,N-nonanoyl-N-methylglycamine, N-octanoyl-N-methyl glutamine,C6-ceramide, dihydro-C6-ceramide, cerabroside, sphingomyelin,galaclocerebrosides, lactocerebrosides, N-acetyl-D-sphingosine,N-hexanoyl-D-sphingosine, N-octonoyl-D-sphingosine,N-lauroyl-D-sphingosine, N-palmitoyl-D-sphingosine,N-oleoyl-D-sphingosine, PEG caprylic/capric diglycerides, PEG8caprylic/capric glycerides, PEG caprylate, PEG8 caprylate, PEG caprate,PEG caproate, glyceryl monocaprylate, glyceryl monocaprate, glycerylmonocaproate, monolaurin, monocaprin, monocaprylin, monomyristin,monopalmitolein, monoolein, creatine, creatinine, agmatine, citrulline,guanidine, sucralose, aspartame, hypoxanthine, theobromine,theophylline, adenine, uracil, uridine, guanine, thymine, thymidine,xanthine, xanthosine, xanthosine monophosphate, pentaerythritolethoxylate, pentaerythritol propoxylate, pentaerythritolpropoxylate/ethoxylate, glycerol ethoxylate, glycerol propoxylate,trimethylolpropane ethoxylate, pentaerythritol, dipentaerythritol, crownether, 18-crown-6, 15-crown-5, 12-crown-4, caffeine, allantoin,(2-hydroxyethyl)urea, N,N′-bis(hydroxymethyl)urea, and combinationsthereof.

In one embodiment of the medical devices, a coating layer overlying theexterior of the medical device includes one or more water-solubleadditives (e.g., a water-soluble first additive, a water-soluble secondadditive, and a water-soluble third additive). In one embodiment, theone or more water-soluble additives are chosen from creatine,creatinine, agmatine, citrulline, guanidine, sucralose, aspartame,hypoxanthine, theobromine, theophylline, adenine, uracil, uridine,guanine, thymine, thymidine, xanthine, xanthosine, xanthosinemonophosphate, caffeine, allantoin, (2-hydroxyethyl)urea,N,N′-bis(hydroxymethyl)urea, pentaerythritol ethoxylate, pentaerythritolpropoxylate, pentaerythritol propoxylate/ethoxylate, glycerolethoxylate, glycerol propoxylate, trimethylolpropane ethoxylate,pentaerythritol, dipentaerythritol, crown ether, 18-crown-6, 15-crown-5,12-crown-4, N-acetylglucosamine, N-octyl-D-gluconamide, C6-ceramide,dihydro-C6-ceramide, cerabroside, sphingomyelin, galaclocerebrosides,lactocerebrosides, N-acetyl-D-sphingosine, N-hexanoyl-D-sphingosine,N-octonoyl-D-sphingosine, N-Lauroyl-D-sphingosine,N-palmitoyl-D-sphingosine, N-oleoyl-D-sphingosine, PEG caprylic/capricdiglycerides, PEG8 caprylic/capric glycerides, PEG caprylate, PEG8caprylate (e.g., Labrasol®), PEG caprate, PEG caproate, glycerylmonocaprylate, glyceryl monocaprate, glyceryl monocaproate, monolaurin,monocaprin, monocaprylin, monomyristin, monopalmitolein, and monoolein.

In one embodiment, the surfactant is chosen from PEG-fatty acids andPEG-fatty acid mono and diesters, polyethylene glycol glycerol fattyacid esters, alcohol-oil transesterification products, polyglycerylfatty acids, propylene glycol fatty acid esters, sterols and derivativesthereof, polyethylene glycol sorbitan fatty acid esters, polyethyleneglycol alkyl ethers, polyethylene glycol alkyl phenols,polyoxyethylene-polyoxypropylene block copolymers, and sorbitan fattyacid esters. In another embodiment, the surfactant is chosen from estersof lauric acid, oleic acid, and stearic acid, PEG-8 laurate, PEG-8oleate, PEG-8 stearate, PEG-9 oleate, PEG-10 laurate, PEG-10 oleate,PEG-12 laurate, PEG-12 oleate, PEG-15 oleate, PEG-20 laurate, PEG-20oleate, PEG-20 dilaurate, PEG-20 dioleate, PEG-20 distearate, PEG-32dilaurate, PEG-32 dioleate, PEG-25 trioleate, PEG-60 corn glycerides,PEG-60 almond oil, PEG-40 palm kernel oil, PEG-8 caprylic/capricglycerides, and PEG-6 caprylic/capric glycerides, PEG-6 corn oil, PEG-6almond oil, PEG-6 apricot kernel oil, PEG-6 olive oil, PEG-6 peanut oil,PEG-6 hydrogenated palm kernel oil, PEG-6 palm kernel oil, PEG-6triolein, PEG-8 corn oil, PEG-20 corn glycerides, PEG-20 almondglycerides, polyglyceryl oleate, polyglyceryl-2 dioleate,polyglyceryl-10 trioleate, polyglyceryl stearate, polyglyceryl laurate,polyglyceryl myristate, polyglyceryl palmitate, and polyglyceryllinoleate, polyglyceryl-10 laurate, polyglyceryl-10 oleate,polyglyceryl-10 mono, dioleate, polyglyceryl-10 stearate,polyglyceryl-10 laurate, polyglyceryl-10 myristate, polyglyceryl-10palmitate, polyglyceryl-10 linoleate, polyglyceryl-6 stearate,polyglyceryl-6 laurate, polyglyceryl-6 myristate, polyglyceryl-6palmitate, and polyglyceryl-6 linoleate, polyglyceryl polyricinoleate,propylene glycol monolaurate, propylene glycol ricinoleate, propyleneglycol monooleate, propylene glycol dicaprylate/dicaprate, propyleneglycol dioctanoate, PEG-20 sorbitan monolaurate, PEG-20 sorbitanmonopalmitate, PEG-20 sorbitan monostearate, PEG-20 sorbitan monooleate,PEG-10-100 nonyl phenol, PEG-15-100 octyl phenol ether, Tyloxapol,octoxynol, nonoxynol, sucrose monopalmitate, sucrose monolaurate,decanoyl-N-methylglucamide, n-decyl-β-D-glucopyranoside,n-decyl-β-D-maltopyranoside, n-dodecyl-β-D-glucopyranoside,n-dodecyl-β-D-maltoside, heptanoyl-N-methylglucamide,n-heptyl-β-D-glucopyranoside, n-heptyl-Q-D-thioglucoside,n-hexyl-β-D-glucopyranoside, nonanoyl-N-methylglucamide,n-nonyl-β-D-glucopyranoside, octanoyl-N-methylglucamide,n-octyl-β-D-glucopyranoside, octyl-β-D-thioglucopyranoside, sorbitanmonolaurate, sorbitan monopalmitate, sorbitan monooleate, sorbitanmonostearate, benzalkonium chloride, benzethonium chloride,cetylpyridinium chloride, docecyl trimethyl ammonium bromide, sodiumdocecylsulfates, dialkyl methylbenzyl ammonium chloride, edrophoniumchloride, domiphen bromide, dialkylesters of sodium sulfonsuccinic acid,sodium dioctyl sulfosuccinate, sodium cholate, sodium taurocholate, andderivatives thereof.

In one embodiment, the additive is chosen from PEG fatty esters andalcohols, glycerol fatty esters, sorbitan fatty esters, PEG glycerylfatty esters, PEG sorbitan fatty esters, sugar fatty esters, PEG sugaresters, vitamins and derivatives, aminoacids, multiaminoacids andderivatives, peptides, polypeptides, proteins, quaternary ammoniumsalts, organic acids, salts and anhydrides. In another embodiment, theadditive in the coating layer overlying the surface of the balloon ischosen from p-isononylphenoxypolyglycidol, PEG laurate, PEG oleate, PEGstearate, PEG glyceryl laurate, PEG glyceryl oleate, PEG glycerylstearate, polyglyceryl laurate, plyglyceryl oleate, polyglycerylmyristate, polyglyceryl palmitate, polyglyceryl-6 laurate, plyglyceryl-6oleate, polyglyceryl-6 myristate, polyglyceryl-6 palmitate,polyglyceryl-10 laurate, plyglyceryl-10 oleate, polyglyceryl-10myristate, polyglyceryl-10 palmitate PEG sorbitan monolaurate, PEGsorbitan monolaurate, PEG sorbitan monooleate, PEG sorbitan stearate,PEG oleyl ether, PEG laurayl ether, octoxynol, monoxynol, tyloxapol,sucrose monopalmitate, sucrose monolaurate, decanoyl-N-methylglucamide,n-decyl-β-D-glucopyranoside, n-decyl-β-D-maltopyranoside,n-dodecyl-β-D-glucopyranoside, n-dodecyl-β-D-maltoside,heptanoyl-N-methylglucamide, n-heptyl-β-D-glucopyranoside,n-heptyl-β-D-thioglucoside, n-hexyl-β-D-glucopyranoside,nonanoyl-N-methylglucamide, n-nonyl-β-D-glucopyranoside,octanoyl-N-methylglucamide, n-octyl-O-D-glucopyranoside,octyl-β-D-thioglucopyranoside; benzalkonium chloride, benzethoniumchloride, docecyl trimethyl ammonium bromide, sodium docecylsulfates,dialkyl methylbenzyl ammonium chloride, and dialkylesters of sodiumsulfonsuccinic acid (ionic surfactants), cystine, tyrosine, tryptophan,leucine, isoleucine, phenylalanine, asparagine, aspartic acid, glutamicacid, and methionine (amino acids); acetic anhydride, benzoic anhydride,ascorbic acid, 2-pyrrolidone-5-carboxylic acid, sodium pyrrolidonecarboxylate, ethylenediaminetetraacetic dianhydride, maleic andanhydride, succinic anhydride, diglycolic anhydride, glutaric anhydride,acetiamine, benfotiamine, pantothenic acid (organic acids andanhydrides), cetotiamine, cycothiamine, dexpanthenol, niacinamide,nicotinic acid, pyridoxal 5-phosphate, nicotinamide ascorbate,riboflavin, riboflavin phosphate, thiamine, folic acid, menadioldiphosphate, menadione sodium bisulfite, menadoxime, vitamin B12,vitamin K5, vitamin K6, vitamin K6, and vitamin U (vitamins); albumin,immunoglobulins, caseins, hemoglobins, lysozymes, immunoglobins,a-2-macroglobulin, fibronectins, vitronectins, firbinogens, lipases,L-ascorbic acid and its salt, D-glucoascorbic acid and its salt,triethanolamine, diethanolamine, meglumine, tromethamine, glucamine,glucosamine, glucoheptonic acid, glucomic acid, gluconolactone,D-glucoheptono-1,4-lactone, glucooctanoic lactone, gulonic acid lactone,mannoic lactone, erythronic acid lactone, ribonic acid lactone,glucosamine, glutamic acid, benzyl alcohol, benzoic acid, hydroxybenzoicacid, vanillin, vanillic acid, vanillic acid diethylamide, lysineacetate salt, gentisic acid, lactobionic acid, lactitol, acetaminophen,ibuprofen, catechin, catechin gallate, methyl paraben, ethyl paraben,propyl paraben, butyl paraben, tiletamine, ketamine, propofol, lacticacids, acetic acid, salts of any organic acid and amine above described,polyglycidol, glycerols and multiglycerols (chemical compounds withmultiple hydroxyl, amino, carbonyl, carboxyl, or ester moieties).

In another embodiment, the medical device further includes adimethylsulfoxide solvent layer, wherein the dimethylsulfoxide solventlayer is overlying the exterior surface of the medical device.

In one embodiment of the medical device, the device is capable ofreleasing the therapeutic agent and the additive and deliveringtherapeutic agent to the tissue in about 0.1 to 10 minutes. In oneembodiment, the concentration of the therapeutic agent in the layer isfrom 1 to 20 μg/mm². In one embodiment, the concentration of thetherapeutic agent in the layer is from 2 to 10 μg/mm². In oneembodiment, the therapeutic agent is not water-soluble (e.g.,hydrophobic).

In one embodiment, the additives enhance release of the therapeuticagent off the balloon. In another embodiment, the additive enhancespenetration and absorption of the therapeutic agent in tissue. Inanother embodiment, the additive has a water and ethanol solubility ofat least 1 mg/ml and the therapeutic agent is not water-soluble.

In another embodiment of the medical device, the layer overlying theexterior surface of the medical device includes a therapeutic agent andat least two additives, wherein each of the additives includes ahydrophilic part and a drug affinity part, wherein the drug affinitypart is at least one of a hydrophobic part, a part that has an affinityto the therapeutic agent by hydrogen bonding, and a part that has anaffinity to the therapeutic agent by van der Waals interactions, andwherein each additive is soluble in polar organic solvent and is solublein water. In one aspect of this embodiment, the polar organic solvent ischosen from methanol, ethanol, isopropanol, acetone, dimethylformide,tetrahydrofuran, methylethyl ketone, dimethylsulfoxide, acetonitrile,ethyl acetate, and chloroform and mixtures of these polar organicsolvents with water. In another aspect of this embodiment, the devicefurther includes a top layer overlying the surface of the layeroverlying the exterior surface of the medical device to reduce loss ofdrug during transit through a body to the target tissue.

In another embodiment of the medical device, the layer overlying theexterior surface of the medical device includes a therapeutic agent andan additive, wherein the additive includes a hydrophilic part and a drugaffinity part, wherein the drug affinity part is at least one of ahydrophobic part, a part that has an affinity to the therapeutic agentby hydrogen bonding, and a part that has an affinity to the therapeuticagent by van der Waals interactions, wherein the additive reducescrystal size and number of particles of the therapeutic agent, andwherein the additive is water-soluble and the therapeutic agent is notwater-soluble.

In another embodiment of the medical device, the layer overlying theexterior surface of the medical device includes a therapeutic agent andan additive, wherein the additive includes a hydrophilic part and a drugaffinity part, wherein the drug affinity part is at least one of ahydrophobic part, a part that has an affinity to the therapeutic agentby hydrogen bonding, and a part that has an affinity to the therapeuticagent by van der Waals interactions, wherein the additive has a fattychain of an acid, ester, ether, or alcohol, wherein the fatty chain candirectly insert into lipid membrane structures of the tissue, andwherein the therapeutic agent is not water-soluble.

In another embodiment of the medical device, the layer overlying theexterior surface of the medical device includes a therapeutic agent andan additive, wherein the additive includes a hydrophilic part and ahydrophobic part, wherein the additive can penetrate into and rearrangelipid membrane structures of the tissue, and wherein the therapeuticagent is not water-soluble. In some embodiments, the therapeutic agentis not enclosed in micelles or encapsulated in polymer particles.

In another embodiment of the medical device, the layer overlying theexterior surface of the medical device includes a therapeutic agent andan additive, wherein the additive includes a hydrophilic part and a drugaffinity part, wherein the additive has a fatty chain of an acid, ester,ether, or alcohol, wherein the fatty chain directly inserts into lipidmembrane structures of tissue, wherein the additive has one or morefunctional groups which have affinity to the drug by hydrogen bondingand/or van der Waals interactions (the functional groups includehydroxyl, ester, amide, carboxylic acid, primary, second, and tertiaryamine, carbonyl, anhydrides, oxides, and amino alcohols), wherein thetherapeutic agent is not water-soluble. In some embodiments, thetherapeutic agent is not enclosed in micelles or encapsulated in polymerparticles. In some embodiments, the layer does not include a polymer,and the layer does not include an iodine covalent bonded contrast agent.

In yet another embodiment, the present invention relates to a medicaldevice coating for delivering a drug to a nonvascular tissue ornonvascular body lumen that is prepared from a mixture. In one aspect ofthis embodiment, the coating is prepared from a mixture including anorganic phase containing drug particles dispersed therein and an aqueousphase containing a water-soluble additive. In one aspect of thisembodiment, the water-soluble additive is chosen from polyethyleneglycol, polyvinyl alcohol, polyvinylpyrrolidinone, polypeptides,water-soluble surfactants, water-soluble vitamins, and proteins. Inanother aspect of this embodiment, the preparation of the mixtureincludes homogenization under high shear conditions and optionally underpressure.

In another embodiment, the present invention relates to a ballooncatheter for delivering a therapeutic agent to a nonvascular body lumen,the catheter including a coating layer overlying an exterior surface ofa balloon. In one embodiment of the balloon catheter, the coating layerincludes a therapeutic agent and an additive, wherein the additiveincludes a hydrophilic part and a drug affinity part, wherein the drugaffinity part is at least one of a hydrophobic part, a part that has anaffinity to the therapeutic agent by hydrogen bonding, and a part thathas an affinity to the therapeutic agent by van der Waals interactions,wherein the additive is water-soluble, and wherein the additive is atleast one of a surfactant and a chemical compound, and wherein thechemical compound has a molecular weight of from 50 to 750.

In another embodiment of the balloon catheter, the coating layerincludes a therapeutic agent and an additive, wherein the additiveincludes a hydrophilic part and a drug affinity part, wherein the drugaffinity part is at least one of a hydrophobic part, a part that has anaffinity to the therapeutic agent by hydrogen bonding, and a part thathas an affinity to the therapeutic agent by van der Waals interactions,wherein the additive is at least one of a surfactant and a chemicalcompound, and wherein the chemical compound has more than four hydroxylgroups. In one aspect of this embodiment, the chemical compound havingmore than four hydroxyl groups has a melting point of 120° C. or less,and the chemical compound is an alcohol or an ester.

In one embodiment of the balloon catheter, the coating layer overlyingan exterior surface of the medical device consists essentially of thetherapeutic agent and the additive. In another embodiment, the coatinglayer overlying an exterior surface of the medical device consistsessentially of a therapeutic agent, a water-soluble first additive and awater-soluble second additive. In another embodiment, the coatingoverlying an exterior surface of the medical device consists essentiallyof a therapeutic agent, and one or more water-soluble additives (e.g., awater-soluble first additive, a water-soluble second additive, and awater-soluble third additive).

In another embodiment, the layer overlying the exterior surface of themedical device does not include an iodine covalent bonded contrastagent.

In one embodiment, the surfactant is chosen from ionic, nonionic,aliphatic, and aromatic surfactants, PEG fatty esters, PEG omega-3 fattyesters, ether, and alcohols, glycerol fatty esters, sorbitan fattyesters, PEG glyceryl fatty esters, PEG sorbitan fatty esters, sugarfatty esters, PEG sugar esters and derivatives thereof. In oneembodiment, the chemical compound has one or more hydroxyl, amino,carbonyl, carboxyl, acid, amide or ester groups. In one embodiment, thechemical compound having one or more hydroxyl, amino, carbonyl,carboxyl, acid, amide or ester groups is chosen from amino alcohols,hydroxyl carboxylic acid, ester, and anhydrides, hydroxyl ketone,hydroxyl lactone, hydroxyl ester, sugar phosphate, sugar sulfate, ethyloxide, ethyl glycols, amino acids, peptides, proteins, sorbitan,glycerol, polyalcohol, phosphates, sulfates, organic acids, esters,salts, vitamins, combinations of amino alcohol and organic acid, andtheir substituted molecules.

In one embodiment of the balloon catheters, the additive is chosen fromPEG-fatty acids and PEG-fatty acid mono and diesters, polyethyleneglycol glycerol fatty acid esters, alcohol-oil transesterificationproducts, polyglyceryl fatty acids, propylene glycol fatty acid esters,sterols and derivatives thereof, polyethylene glycol sorbitan fatty acidesters, polyethylene glycol alkyl ethers, sugars and derivativesthereof, polyethylene glycol alkyl phenols,polyoxyethylene-polyoxypropylene block copolymers, sorbitan fatty acidesters, fat-soluble vitamins and salts thereof, water-soluble vitaminsand amphiphilic derivatives thereof, amino acid and salts thereof,oligopeptides, peptides and proteins, and organic acids and esters andanhydrides thereof.

In another embodiment of the balloon catheters, the additive is chosenfrom esters of lauric acid, oleic acid, and stearic acid, PEG-8 laurate,PEG-8 oleate, PEG-8 stearate, PEG-9 oleate, PEG-10 laurate, PEG-10oleate, PEG-12 laurate, PEG-12 oleate, PEG-15 oleate, PEG-20 laurate,and PEG-20 oleate. In another embodiment, the additive is chosen fromPEG-20 dilaurate, PEG-20 dioleate, PEG-20 distearate, PEG-32 dilaurateand PEG-32 dioleate. In another embodiment of the method, the additiveis chosen from PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-40glyceryl laurate, PEG-20 glyceryl oleate, and PEG-30 glyceryl oleate. Inanother embodiment of the method, the additive is chosen from PEG-25trioleate, PEG-60 corn glycerides, PEG-60 almond oil, PEG-40 palm kerneloil, PEG-8 caprylic/capric glycerides, and PEG-6 caprylic/capricglycerides, PEG-6 corn oil, PEG-6 almond oil, PEG-6 apricot kernel oil,PEG-6 olive oil, PEG-6 peanut oil, PEG-6 hydrogenated palm kernel oil,PEG-6 palm kernel oil, PEG-6 triolein, PEG-8 corn oil, PEG-20 cornglycerides, and PEG-20 almond glycerides.

In another embodiment of the balloon catheters, the additive is chosenfrom polyglyceryl oleate, polyglyceryl-2 dioleate, polyglyceryl-10trioleate, polyglyceryl stearate, polyglyceryl laurate, polyglycerylmyristate, polyglyceryl palmitate, and polyglyceryl linoleate,polyglyceryl-10 laurate, polyglyceryl-10 oleate, polyglyceryl-10 mono,dioleate, polyglyceryl-10 stearate, polyglyceryl-10 laurate,polyglyceryl-10 myristate, polyglyceryl-10 palmitate, polyglyceryl-10linoleate, polyglyceryl-6 stearate, polyglyceryl-6 laurate,polyglyceryl-6 myristate, polyglyceryl-6 palmitate, and polyglyceryl-6linoleate, and polyglyceryl polyricinoleate. In another embodiment ofthe method, the additive is chosen from propylene glycol monolaurate,propylene glycol ricinoleate, propylene glycol monooleate, propyleneglycol dicaprylate/dicaprate, and propylene glycol dioctanoate. Inanother embodiment of the balloon catheters, the additive is PEG-24cholesterol ether. In another embodiment of the balloon catheters, theadditive is chosen from sterol polyethylene glycol derivatives.

In one embodiment, the present invention relates to a method fortreating a stricture in a nonvascular body lumen including inserting aballoon catheter including a coating layer into an body stricture,wherein the stricture is one of urethral strictures, benign prostatichyperplasia (BPH) strictures, ureteral strictures, esophagealstrictures, sinus strictures, and biliary tract strictures, wherein thecoating layer includes a drug and an additive, inflating the ballooncatheter and releasing the drug to a wall of the stricture, deflatingthe balloon; and withdrawing the balloon catheter, wherein the residualdrug is about 1 to 70% of the total loading drug on the ballooncatheter. In one aspect of this embodiment, the additive enhancesabsorption of the drug into tissue of the nonvascular body lumen. Inanother embodiment of the method, the additive is chosen from PEG-20sorbitan monolaurate, PEG-20 sorbitan monopalmitate, PEG-20 sorbitanmonostearate, and PEG-20 sorbitan monooleate. In another embodiment ofthe method, the additive is chosen from PEG-3 oleyl ether and PEG-4lauryl ether. In another embodiment of the method, the additive ischosen from sucrose monopalmitate, sucrose monolaurate,decanoyl-N-methylglucamide, n-decyl-β-D-glucopyranoside,n-decyl-β-D-maltopyranoside, n-dodecyl-β-D-glucopyranoside,n-dodecyl-β-D-maltoside, heptanoyl-N-methylglucamide,n-heptyl-β-D-glucopyranoside, n-heptyl-Q-D-thioglucoside,n-hexyl-β-D-glucopyranoside, nonanoyl-N-methylglucamide,n-nonyl-β-D-glucopyranoside, octanoyl-N-methylglucamide,n-octyl-β-D-glucopyranoside, and octyl-O-D-thioglucopyranoside.

In another embodiment of the method, the additive is chosen fromPEG-10-100 nonyl phenol, PEG-15-100 octyl phenol ether, Tyloxapol,octoxynol, and nonoxynol. In another embodiment of the method, theadditive is chosen from poloxamer 108, poloxamer 188, poloxamer 217,poloxamer 238, poloxamer 288, poloxamer 338, and poloxamer 407. Inanother embodiment of the method, the additive is chosen from poloxamer124, poloxamer 182, poloxamer 183, poloxamer 212, poloxamer 331, andpoloxamer 335. In another embodiment of the method, the additive ischosen from sorbitan monolaurate, sorbitan monopalmitate, sorbitanmonooleate, and sorbitan monostearate. In another embodiment of themethod, the additive is chosen from alpha-tocopherol, beta-tocopherol,gamma-tocopherol, delta-tocopherol, tocopherol acetate, ergosterol,1-alpha-hydroxycholecal-ciferol, vitamin D2, vitamin D3, alpha-carotene,beta-carotene, gamma-carotene, vitamin A, fursultiamine,methylolriboflavin, octotiamine, prosultiamine, riboflavine, vintiamol,dihydrovitamin K1, menadiol diacetate, menadiol dibutyrate, menadioldisulfate, menadiol, vitamin K1, vitamin K1 oxide, vitamins K2, andvitamin K-S(II), and folic acid.

In another embodiment of the method, the additive is chosen fromacetiamine, benfotiamine, pantothenic acid, cetotiamine, cycothiamine,dexpanthenol, niacinamide, nicotinic acid, pyridoxal 5-phosphate,nicotinamide ascorbate, riboflavin, riboflavin phosphate, thiamine,folic acid, menadiol diphosphate, menadione sodium bisulfite,menadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin K6, and vitaminU. In another embodiment of the method, the additive is chosen fromalanine, arginine, asparagines, aspartic acid, cysteine, glutamic acid,glutamine, glycine, histidine, proline, isoleucine, leucine, lysine,methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, andvaline, and salts of any of the foregoing. In another embodiment of themethod, the additive is albumin. In another embodiment of the method,the additive is chosen from n-octyl-β-D-glucopyranoside, octoxynol-9,Polysorbates, Tyloxapol, octoxynol, nonoxynol,isononylphenylpolyglycidol, PEG glyceryl monooleate, sorbitanmonolaurate, sorbitan monopalmitate, sorbitan monooleate, sorbitanmonostearate, polyglyceryl-10 oleate, polyglyceryl-10 laurate,polyglyceryl-10 palmitate, polyglyceryl-10 stearate, L-ascorbic acid,thiamine, maleic anhydride, niacinamide, and 2-pyrrolidone-5-carboxylicacid.

In another embodiment of the method, the additive is chosen fromisononylphenylpolyglycidol, PEG glyceryl monooleate, sorbitanmonolaurate, sorbitan monopalmitate, sorbitan monooleate, sorbitanmonostearate, polyglyceryl-10 oleate, polyglyceryl-10 laurate,polyglyceryl-10 palmitate, and polyglyceryl-10 stearate. In anotherembodiment of the method, the additive is chosen from L-ascorbic acid,thiamine, maleic acids, niacinamide, and 2-pyrrolidone-5-carboxylicacid. In another embodiment of the method, the additive is chosen fromVitamin D2 and D3.

In one embodiment, the additive is at least one of a surfactant and achemical compound. In one embodiment, the chemical compound is chosenfrom amino alcohols, hydroxyl carboxylic acid, ester, anhydrides,hydroxyl ketone, hydroxyl lactone, hydroxyl ester, sugar phosphate,sugar sulfate, ethyl oxide, ethyl glycols, amino acids, peptides,proteins, sorbitan, glycerol, polyalcohol, phosphates, sulfates, organicacids, esters, salts, vitamins, combinations of amino alcohol andorganic acid, and their substituted molecules. In one embodiment, thesurfactant is chosen from ionic, nonionic, aliphatic, and aromaticsurfactants, PEG fatty esters, PEG omega-3 fatty esters, ether, andalcohols, glycerol fatty esters, sorbitan fatty esters, PEG glycerylfatty esters, PEG sorbitan fatty esters, sugar fatty esters, PEG sugaresters, and derivatives thereof. In one embodiment, the chemicalcompound has one or more hydroxyl, amino, carbonyl, carboxyl, acid,amide or ester groups. In one aspect of this embodiment, the chemicalcompound having one or more hydroxyl, amino, carbonyl, carboxyl, acid,amide or ester groups is chosen from amino alcohols, hydroxyl carboxylicacid, ester, anhydrides, hydroxyl ketone, hydroxyl lactone, hydroxylester, sugar phosphate, sugar sulfate, ethyl oxide, ethyl glycols, aminoacids, peptides, proteins, sorbitan, glycerol, polyalcohol, phosphates,sulfates, organic acids, esters, salts, vitamins, combinations of aminoalcohol and organic acid, and their substituted molecules. In oneembodiment, the additive is chosen from p-isononylphenoxypolyglycidol,PEG laurate, Tween 20, Tween 40, Tween 60, Tween 80, PEG oleate, PEGstearate, PEG glyceryl laurate, PEG glyceryl oleate, PEG glycerylstearate, polyglyceryl laurate, plyglyceryl oleate, polyglycerylmyristate, polyglyceryl palmitate, polyglyceryl-6 laurate, plyglyceryl-6oleate, polyglyceryl-6 myristate, polyglyceryl-6 palmitate,polyglyceryl-10 laurate, plyglyceryl-10 oleate, polyglyceryl-10myristate, polyglyceryl-10 palmitate PEG sorbitan monolaurate, PEGsorbitan monolaurate, PEG sorbitan monooleate, PEG sorbitan stearate,PEG oleyl ether, PEG laurayl ether, octoxynol, monoxynol, tyloxapol,sucrose monopalmitate, sucrose monolaurate, decanoyl-N-methylglucamide,n-decyl-β-D-glucopyranoside, n-decyl-β-D-maltopyranoside,n-dodecyl-β-D-glucopyranoside, n-dodecyl-β-D-maltoside,heptanoyl-N-methylglucamide, n-heptyl-β-D-glucopyranoside,n-heptyl-Q-D-thioglucoside, n-hexyl-β-D-glucopyranoside,nonanoyl-N-methylglucamide, n-nonyl-β-D-glucopyranoside,octanoyl-N-methylglucamide, n-octyl-β-D-glucopyranoside,octyl-β-D-thioglucopyranoside, vanillin, methyl paraben, propyl paraben,sorbitol, xylitol, cyclodextrin, (2-hydroxypropyl)-cyclodextrin,acetaminophen, ibuprofen, retinoic acid, lysine acetate, gentisic acid,catechin, catechin gallate, tiletamine, ketamine, propofol, lacticacids, acetic acid, salts of any organic acid and organic amine,polyglycidol, glycerol, multiglycerols, galactitol, di(ethylene glycol),tri(ethylene glycol), tetra(ethylene glycol), penta(ethylene glycol),poly(ethylene glycol) oligomers, di(propylene glycol), tri(propyleneglycol), tetra(propylene glycol, and penta(propylene glycol),poly(propylene glycol) oligomers, a block copolymer of polyethyleneglycol and polypropylene glycol, and derivatives and combinationsthereof.

In one embodiment, the additive is chosen from PEG-fatty acids andPEG-fatty acid mono and diesters, polyethylene glycol glycerol fattyacid esters, alcohol-oil transesterification products, polyglycerylfatty acids, propylene glycol fatty acid esters, sterol and derivativesthereof, polyethylene glycol sorbitan fatty acid esters, polyethyleneglycol alkyl ethers, sugars and derivatives thereof, polyethylene glycolalkyl phenols, polyoxyethylene-polyoxypropylene block copolymers,sorbitan fatty acid esters, fat-soluble vitamins and salts thereof,water-soluble vitamins and amphiphilic derivatives thereof, amino acidand salts thereof, oligopeptides, peptides and proteins, and organicacids and esters and anhydrides thereof. In yet another aspect of thisembodiment, the water insoluble drug is chosen from paclitaxel andanalogues thereof and rapamycin and analogues thereof.

In one embodiment, the surfactant is chosen from esters of lauric acid,oleic acid, and stearic acid, PEG-8 laurate, PEG-8 oleate, PEG-8stearate, PEG-9 oleate, PEG-10 laurate, PEG-10 oleate, PEG-12 laurate,PEG-12 oleate, PEG-15 oleate, PEG-20 laurate, PEG-20 oleate, PEG-20dilaurate, PEG-20 dioleate, PEG-20 distearate, PEG-32 dilaurate, PEG-32dioleate, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-40glyceryl laurate, PEG-20 glyceryl oleate, PEG-30 glyceryl oleate, PEG-25trioleate, PEG-60 corn glycerides, PEG-60 almond oil, PEG-40 palm kerneloil, PEG-8 caprylic/capric glycerides, PEG-6 caprylic/capric glycerides,PEG-6 corn oil, PEG-6 almond oil, PEG-6 apricot kernel oil, PEG-6 oliveoil, PEG-6 peanut oil, PEG-6 hydrogenated palm kernel oil, PEG-6 palmkernel oil, PEG-6 triolein, PEG-8 corn oil, PEG-20 corn glycerides,PEG-20 almond glycerides, polyglyceryl oleate, polyglyceryl-2 dioleate,polyglyceryl-10 trioleate, polyglyceryl stearate, polyglyceryl laurate,polyglyceryl myristate, polyglyceryl palmitate, and polyglyceryllinoleate, polyglyceryl-10 laurate, polyglyceryl-10 oleate,polyglyceryl-10 mono, dioleate, polyglyceryl-10 stearate,polyglyceryl-10 laurate, polyglyceryl-10 myristate, polyglyceryl-10palmitate, polyglyceryl-10 linoleate, polyglyceryl-6 stearate,polyglyceryl-6 laurate, polyglyceryl-6 myristate, polyglyceryl-6palmitate, and polyglyceryl-6 linoleate, and polyglycerylpolyricinoleate, propylene glycol monolaurate, propylene glycolricinoleate, propylene glycol monooleate, propylene glycoldicaprylate/dicaprate, propylene glycol dioctanoate, PEG-20 sorbitanmonolaurate, PEG-20 sorbitan monopalmitate, PEG-20 sorbitanmonostearate, PEG-20 sorbitan monooleate, PEG-3 oleyl ether and PEG-4lauryl ether, sucrose monopalmitate, sucrose monolaurate,decanoyl-N-methylglucamide, n-decyl-β-D-glucopyranoside,n-decyl-β-D-maltopyranoside, n-dodecyl-β-D-glucopyranoside,n-dodecyl-β-D-maltoside, heptanoyl-N-methylglucamide,n-heptyl-β-D-glucopyranoside, n-heptyl-β-D-thioglucoside,n-hexyl-β-D-glucopyranoside, nonanoyl-N-methylglucamide,n-nonyl-Q-D-glucopyranoside, octanoyl-N-methylglucamide,n-octyl-β-D-glucopyranoside, octyl-β-D-thioglucopyranoside, PEG-10-100nonyl phenol, PEG-15-100 octyl phenol ether, Tyloxapol, octoxynol,nonoxynol, sorbitan monolaurate, sorbitan monopalmitate, sorbitanmonooleate, sorbitan monostearate, benzalkonium chloride, benzethoniumchloride, docecyl trimethyl ammonium bromide, sodium docecylsulfates,dialkyl methylbenzyl ammonium chloride, and dialkylesters of sodiumsulfonsuccinic acid (ionic surfactants), n-octyl-β-D-glucopyranoside,octoxynol-9, Polysorbates, Tyloxapol, octoxynol, nonoxynol,isononylphenylpolyglycidol, PEG glyceryl monooleate, sorbitanmonolaurate, sorbitan monopalmitate, sorbitan monooleate, sorbitanmonostearate, polyglyceryl-10 oleate, polyglyceryl-10 laurate,polyglyceryl-10 palmitate, polyglyceryl-10 stearate, and theirderivatives.

In one embodiment, the water insoluble drug is chosen from paclitaxeland analogues thereof and rapamycin and analogues thereof.

In one embodiment, some drugs that are considered particularly suitablefor the airway, sinus and other nasal lumens are corticosteroids suchas, budesonide, flunisolide, triamcinolone, beclomethasone, fluticasone,mometasone, mometasone furoate, dexamethasone, hydrocortisone,methylprednisolone, prednisone, cortisone, betamethasone, triamcinoloneacetonide, or the like.

In one embodiment, the present invention relates to a method fortreating a nonvascular body lumen including inserting a balloon catheterincluding a coating layer into an body lumen, wherein the body lumen isone of esophagus, airways, sinus, trachea, colon, biliary tract, urinarytract, prostate, urethral, ureteral, and other nonvascular lumens,wherein the coating layer includes a drug and an additive, inflating theballoon catheter and releasing the drug to a wall of the body lumen,deflating the balloon; and withdrawing the balloon catheter. In anotherembodiment, the present invention relates to a method for treating astricture in a nonvascular body lumen including flushing the lumen withwater, saline solution, or water solutions of the additives describedabove, inserting a balloon catheter including a coating layer into anbody lumen, wherein the body lumen is one of esophagus, airways, sinus,trachea, colon, biliary tract, urinary tract, prostate, urethral,ureteral, and other nonvascular lumens, wherein the coating layerincludes a drug and an additive, inflating the balloon catheter andreleasing the drug to a wall of the body lumen, deflating the balloon,and withdrawing the balloon catheter. In another embodiment, the presentinvention relates to a method for treating a stricture in a nonvascularbody lumen including infusing water, saline solution, or a watersolution including at least one of the additives described above,inserting a balloon catheter including a coating layer into a stricturein a nonvascular body lumen, wherein the stricture in the nonvascularbody lumen is one of, urethral strictures, ureteral strictures,esophageal strictures, sinus strictures, and biliary tract strictures,wherein the coating layer includes a drug and an additive, inflating theballoon catheter and releasing the drug to a wall of the stricture in anonvascular body lumen, deflating the balloon, flushing the lumen withwater or saline solution, and withdrawing the balloon catheter. In oneaspect of this embodiment, the additive enhances absorption of the druginto tissue of the nonvascular body lumens. In another aspect of thisembodiment, the additive includes a hydrophilic part and a drug affinitypart, wherein the drug affinity part is at least one of a hydrophobicpart, a part that has an affinity to the therapeutic agent by hydrogenbonding, and a part that has an affinity to the therapeutic agent by vander Waals interactions. In another aspect of this embodiment, the drugis not enclosed in micelles or encapsulated in polymer particles. Inanother aspect of this embodiment, the coating layer does not includeoil, a lipid, or a polymer. In another aspect of this embodiment, thecoating layer does not include a purely hydrophobic additive. In anotheraspect of this embodiment, the drug is chosen from paclitaxel andanalogues thereof and rapamycin and analogues thereof. In another aspectof this embodiment, the additive is chosen from PEG-fatty acids andPEG-fatty acid mono and diesters, polyethylene glycol glycerol fattyacid esters, alcohol-oil transesterification products, polyglycerylfatty acids, propylene glycol fatty acid esters, sterol and derivativesthereof, polyethylene glycol sorbitan fatty acid esters, polyethyleneglycol alkyl ethers, sugars and derivatives thereof, polyethylene glycolalkyl phenols, polyoxyethylene-polyoxypropylene block copolymers,sorbitan fatty acid esters, fat-soluble vitamins and salts thereof,water-soluble vitamins and amphiphilic derivatives thereof, amino acidand salts thereof, oligopeptides, peptides and proteins, and organicacids and esters and anhydrides thereof. In yet another aspect of thisembodiment, the drug can be released to the wall of the airway prior to,during, or after an asthma attack. In yet another aspect of thisembodiment, the drug can be released to the wall of the esophagus. Inyet another aspect of this embodiment, the drug can be released to thewall of the sinus. In yet another aspect of this embodiment, the drugcan be released to the wall of the biliary tract. In yet another aspectof this embodiment, the drug can be released to the wall of the urinarytract, prostate, urethral, and ureteral lumens.

In one embodiment, the additive is at least one of a surfactant and achemical compound. In one embodiment, the chemical compound is chosenfrom amino alcohols, hydroxyl carboxylic acid, ester, anhydrides,hydroxyl ketone, hydroxyl lactone, hydroxyl ester, sugar phosphate,sugar sulfate, ethyl oxide, ethyl glycols, amino acids, peptides,proteins, sorbitan, glycerol, polyalcohol, phosphates, sulfates, organicacids, esters, salts, vitamins, combinations of amino alcohol andorganic acid, and their substituted molecules. In one embodiment, thesurfactant is chosen from ionic, nonionic, aliphatic, and aromaticsurfactants, PEG fatty esters, PEG omega-3 fatty esters, ether, andalcohols, glycerol fatty esters, sorbitan fatty esters, PEG glycerylfatty esters, PEG sorbitan fatty esters, sugar fatty esters, PEG sugaresters, and derivatives thereof.

In one embodiment, the chemical compound has one or more hydroxyl,amino, carbonyl, carboxyl, acid, amide or ester groups. In one aspect ofthis embodiment, the chemical compound having one or more hydroxyl,amino, carbonyl, carboxyl, acid, amide or ester groups is chosen fromamino alcohols, hydroxyl carboxylic acid, ester, anhydrides, hydroxylketone, hydroxyl lactone, hydroxyl ester, sugar phosphate, sugarsulfate, ethyl oxide, ethyl glycols, amino acids, peptides, proteins,sorbitan, glycerol, polyalcohol, phosphates, sulfates, organic acids,esters, salts, vitamins, combinations of amino alcohol and organic acid,and their substituted molecules.

In one embodiment, the additive is chosen fromp-isononylphenoxypolyglycidol, PEG laurate, Tween 20, Tween 40, Tween60, PEG oleate, PEG stearate, PEG glyceryl laurate, PEG glyceryl oleate,PEG glyceryl stearate, polyglyceryl laurate, plyglyceryl oleate,polyglyceryl myristate, polyglyceryl palmitate, polyglyceryl-6 laurate,plyglyceryl-6 oleate, polyglyceryl-6 myristate, polyglyceryl-6palmitate, polyglyceryl-10 laurate, plyglyceryl-10 oleate,polyglyceryl-10 myristate, polyglyceryl-10 palmitate PEG sorbitanmonolaurate, PEG sorbitan monolaurate, PEG sorbitan monooleate, PEGsorbitan stearate, PEG oleyl ether, PEG laurayl ether, octoxynol,monoxynol, tyloxapol, sucrose monopalmitate, sucrose monolaurate,decanoyl-N-methylglucamide, n-decyl-β-D-glucopyranoside,n-decyl-β-D-maltopyranoside, n-dodecyl-β-D-glucopyranoside,n-dodecyl-β-D-maltoside, heptanoyl-N-methylglucamide,n-heptyl-β-D-glucopyranoside, n-heptyl-Q-D-thioglucoside,n-hexyl-β-D-glucopyranoside, nonanoyl-N-methylglucamide,n-nonyl-β-D-glucopyranoside, octanoyl-N-methylglucamide,n-octyl-β-D-glucopyranoside, octyl-β-D-thioglucopyranoside, cystine,tyrosine, tryptophan, leucine, isoleucine, phenylalanine, asparagine,aspartic acid, glutamic acid, and methionine; acetic anhydride, benzoicanhydride, ascorbic acid, 2-pyrrolidone-5-carboxylic acid, sodiumpyrrolidone carboxylate, ethylenediaminetetraacetic dianhydride, maleicand anhydride, succinic anhydride, diglycolic anhydride, glutaricanhydride, acetiamine, benfotiamine, pantothenic acid, cetotiamine,cycothiamine, dexpanthenol, niacinamide, nicotinic acid, pyridoxal5-phosphate, nicotinamide ascorbate, riboflavin, riboflavin phosphate,thiamine, folic acid, menadiol diphosphate, menadione sodium bisulfite,menadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin K6, and vitaminU; albumin, immunoglobulins, caseins, hemoglobins, lysozymes,immunoglobins, a-2-macroglobulin, fibronectins, vitronectins,firbinogens, lipases, benzalkonium chloride, benzethonium chloride,docecyl trimethyl ammonium bromide, sodium docecylsulfates, dialkylmethylbenzyl ammonium chloride, and dialkylesters of sodiumsulfonsuccinic acid, L-ascorbic acid and its salt, D-glucoascorbic acidand its salt, tromethamine, triethanolamine, diethanolamine, meglumine,glucamine, amine alcohols, glucoheptonic acid, glucomic acid, hydroxylketone, hydroxyl lactone, gluconolactone, glucoheptonolactone,glucooctanoic lactone, gulonic acid lactone, mannoic lactone, ribonicacid lactone, lactobionic acid, glucosamine, glutamic acid, benzylalcohol, benzoic acid, hydroxybenzoic acid, propyl 4-hydroxybenzoate,lysine acetate salt, gentisic acid, lactobionic acid, lactitol, sinapicacid, vanillic acid, vanillin, methyl paraben, propyl paraben, sorbitol,xylitol, cyclodextrin, (2-hydroxypropyl)-cyclodextrin, acetaminophen,ibuprofen, retinoic acid, lysine acetate, gentisic acid, catechin,catechin gallate, tiletamine, ketamine, propofol, lactic acids, aceticacid, salts of any organic acid and organic amine, polyglycidol,glycerol, multiglycerols, galactitol, di(ethylene glycol), tri(ethyleneglycol), tetra(ethylene glycol), penta(ethylene glycol), poly(ethyleneglycol) oligomers, di(propylene glycol), tri(propylene glycol),tetra(propylene glycol, and penta(propylene glycol), poly(propyleneglycol) oligomers, a block copolymer of polyethylene glycol andpolypropylene glycol, and derivatives and combinations thereof.

It is understood that both the foregoing general description and thefollowing detailed description are exemplary and explanatory only andare not restrictive of the present invention as claimed.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a perspective view of an exemplary embodiment of a ballooncatheter according to the present invention.

FIGS. 2A-2C are cross-sectional views of different embodiments of thedistal portion of the balloon catheter of FIG. 1 , taken along line A-A,showing exemplary coating layers.

DETAILED DESCRIPTION OF THE INVENTION

Reference will now be made in detail to certain embodiments of thedisclosed subject matter, examples of which are illustrated in part inthe accompanying drawings. While the disclosed subject matter will bedescribed in conjunction with the enumerated claims, it will beunderstood that the exemplified subject matter is not intended to limitthe claims to the disclosed subject matter.

Throughout this document, values expressed in a range format should beinterpreted in a flexible manner to include not only the numericalvalues explicitly recited as the limits of the range, but also toinclude all the individual numerical values or sub-ranges encompassedwithin that range as if each numerical value and sub-range is explicitlyrecited. For example, a range of “about 0.1% to about 5%” or “about 0.1%to 5%” should be interpreted to include not just about 0.1% to about 5%,but also the individual values (e.g., 1%, 2%, 3%, and 4%) and thesub-ranges (e.g., 0.1% to 0.5%, 1.1% to 2.2%, 3.3% to 4.4%) within theindicated range. The statement “about X to Y” has the same meaning as“about X to about Y,” unless indicated otherwise. Likewise, thestatement “about X, Y, or about Z” has the same meaning as “about X,about Y, or about Z,” unless indicated otherwise.

In this document, the terms “a,” “an,” or “the” are used to include oneor more than one unless the context clearly dictates otherwise. The term“or” is used to refer to a nonexclusive “or” unless otherwise indicated.The statement “at least one of A and B” has the same meaning as “A, B,or A and B.” In addition, it is to be understood that the phraseology orterminology employed herein, and not otherwise defined, is for thepurpose of description only and not of limitation. Any use of sectionheadings is intended to aid reading of the document and is not to beinterpreted as limiting; information that is relevant to a sectionheading may occur within or outside of that particular section.

In the methods described herein, the acts can be carried out in anyorder without departing from the principles of the invention, exceptwhen a temporal or operational sequence is explicitly recited.Furthermore, specified acts can be carried out concurrently unlessexplicit claim language recites that they be carried out separately. Forexample, a claimed act of doing X and a claimed act of doing Y can beconducted simultaneously within a single operation, and the resultingprocess will fall within the literal scope of the claimed process.

The term “about” as used herein can allow for a degree of variability ina value or range, for example, within 10%, within 5%, or within 1% of astated value or of a stated limit of a range, and includes the exactstated value or range.

The term “substantially” as used herein refers to a majority of, ormostly, as in at least about 50%, 60%/, 70%, 80%, 90%, 95%, 96%, 97%,98%, 99%, 99.5%, 99.9%, 99.99%, or at least about 99.999% or more, or100%.

Embodiments of the present invention relate to medical devices,including particularly balloon catheters and stents, having a rapiddrug-releasing coating and methods for preparing such coated devices.The therapeutic agent according to embodiments of the present inventiondoes not require a delayed or long term release and instead, forexample, the therapeutic agent and the additive are released in a veryshort time period to provide a therapeutic effect upon contact withtissue. An object of embodiments of the present invention is tofacilitate rapid and efficient uptake of drug by target tissue duringtransitory device deployment at a target site.

As shown in FIG. 1 , in one embodiment, the medical device is a ballooncatheter. The balloon catheter may be any suitable catheter for thedesired use, including conventional balloon catheters known to one ofordinary skill in the art. For example, balloon catheter 10 may includean expandable, inflatable balloon 12 at a distal end of the catheter 10,a handle assembly 16 at a proximal end of the catheter 10, and anelongate flexible member 14 extending between the proximal and distalends. Handle assembly 16 may connect to and/or receive one or moresuitable medical devices, such as a source of inflation media (e.g.,air, saline, or contrast media). Flexible member 14 may be a tube madeof suitable biocompatible material and having one or more lumenstherein. At least one of the lumens is configured to receive inflationmedia and pass such media to balloon 12 for its expansion. The ballooncatheter may be a rapid exchange or over-the-wire catheter and made ofany suitable biocompatible material. The material of balloon 12 caninclude one or more of polyesters, polyamides, nylon 12, nylon 11,polyamide 12, block copolymers of polyether and polyamide, Pebax,polyurethanes, and block copolymers of polyether and polyester.

In one embodiment, the present invention provides a medical device fordelivering a therapeutic agent to a tissue, such as a vascular tissue ora nonvascular tissue. The device includes a layer applied to an exteriorsurface of the medical device, such as a balloon catheter or stent, forexample. The layer includes a therapeutic agent and one or moreadditives. The additive can be any suitable additive. The layer caninclude one additive, or the layer can include more than one additive,such as a water-soluble first additive and a water-soluble secondadditive. For example, as shown in the embodiment depicted in FIG. 2A,the balloon 12 is coated with a layer 20 that includes a therapeuticagent and an additive. In some embodiments, the layer consistsessentially of a therapeutic agent and an additive, i.e., the layerincludes only the therapeutic agent and the additive, without any othermaterially significant components. In some embodiments, the device mayoptionally include an adherent layer. For example, as shown in theembodiment depicted in FIG. 2B, the balloon 12 is coated with anadherent layer 22. A layer 24 that includes a therapeutic agent and anadditive is overlying the adherent layer. The adherent layer, which is aseparate layer underlying the drug coating layer, improves the adherenceof the drug coating layer to the exterior surface of the medical deviceand protects coating integrity. For example, if drug and additive differin their adherence to the medical device, the adherent layer may preventdifferential loss of components and maintain drug-to-additive ratio inthe coating during transit to a target site for therapeuticintervention. Furthermore, the adherent layer may function to facilitaterapid release of coating layer components off the device surface uponcontact with tissues at the target site. In other embodiments, thedevice may include a top layer. The top layer may reduce loss of thedrug layer before it is brought into contact with target tissues, forexample during transit of the balloon 12 to the site of therapeuticintervention or during the first moments of inflation of balloon 12before coating layer 20 is pressed into direct contact with targettissue.

Embodiments of the present invention are directed to the treatment ofstrictures in nonvascular body lumens by delivering of an effectiveamount of anti-inflammatory and anti-proliferate drugs (e.g., rapamycin,paclitaxel, or their analogues). The strictures in a nonvascular bodylumen include urethral strictures, ureteral strictures, esophagealstrictures, sinus strictures, and biliary tract strictures. Embodimentsof the present invention are directed to methods for treating at leastone of benign prostatic hyperplasia (BPH), prostate cancer, asthma, andchronic obstructive pulmonary disease (COPD). According to embodiments,the method involves delivering of anti-inflammatory and anti-proliferatedrugs (e.g., rapamycin, paclitaxel, or their analogues) via coatedmedical devices, such as balloon catheters and stents. Theanti-inflammatory and anti-proliferate drugs can be coated with themedical device alone or with one or more additives.

In one embodiment, the present invention relates to a method fortreating a stricture in a nonvascular body lumen including inserting aballoon catheter including a coating layer into the stricture, whereinthe stricture is one of urethral strictures, ureteral strictures,esophageal strictures, sinus strictures, and biliary tract strictures,wherein the coating layer includes a drug and an additive, inflating theballoon catheter and releasing the drug to a wall of the stricture,deflating the balloon; and withdrawing the balloon catheter, wherein theresidual drug is about 1 to 70% of the total loading drug on the ballooncatheter, wherein the drug in the wall of body lumen is about 0.1 to 25%of the total loading drug on the balloon catheter. In one aspect of thisembodiment, the additive enhances absorption of the drug into tissue ofthe stricture in the nonvascular body lumen.

In one embodiment, the present invention relates to a method fortreating a nonvascular body lumen including inserting a balloon catheterincluding a coating layer into an body lumen, wherein the body lumen isone of esophagus, airways, sinus, trachea, colon, biliary tract, urinarytract, prostate, urethral, ureteral, and other nonvascular lumens,wherein the coating layer includes a drug and an additive, inflating theballoon catheter and releasing the drug to a wall of the nonvascularbody lumen, deflating the balloon; and withdrawing the balloon catheter,wherein the residual drug is about 1 to 70% of the total loading drug onthe balloon catheter, wherein the drug in the wall of body lumen isabout 0.1 to 25% of the total loading drug on the balloon catheter. Inone aspect of this embodiment, the additive enhances absorption of thedrug into tissue of the nonvascular body lumens. In another aspect ofthis embodiment, the additive includes a hydrophilic part and a drugaffinity part, wherein the drug affinity part is at least one of ahydrophobic part, a part that has an affinity to the therapeutic agentby hydrogen bonding, and a part that has an affinity to the therapeuticagent by van der Waals interactions.

In one embodiment, the present invention relates to a balloon catheterfor delivering a therapeutic agent to a target site of a nonvascularbody lumen, the balloon catheter including a coating layer overlying anexterior surface of a balloon, wherein the coating layer includes aninitial drug load of a hydrophobic therapeutic agent, and one or morewater-soluble additive; the hydrophobic therapeutic agent is selectedfrom the group consisting of paclitaxel, paclitaxel analogues,rapamycin, rapamycin analogues, and combinations thereof; thewater-soluble additive is selected from the group consisting ofN-acetylglucosamine, N-octyl-D-gluconamide,N-nonanoyl-N-methylglycamine, N-octanoyl-N-methyl glutamine,C6-ceramide, dihydro-C6-ceramide, cerabroside, sphingomyelin,galaclocerebrosides, lactocerebrosides, N-acetyl-D-sphingosine,N-hexanoyl-D-sphingosine, N-octonoyl-D-sphingosine,N-lauroyl-D-sphingosine, N-palmitoyl-D-sphingosine,N-oleoyl-D-sphingosine, PEG caprylic/capric diglycerides, PEG8caprylic/capric glycerides, PEG caprylate, PEG8 caprylate, PEG caprate,PEG caproate, glyceryl monocaprylate, glyceryl monocaprate, glycerylmonocaproate, monolaurin, monocaprin, monocaprylin, monomyristin,monopalmitolein, monoolein, creatine, creatinine, agmatine, citrulline,guanidine, sucralose, aspartame, hypoxanthine, theobromine,theophylline, adenine, uracil, uridine, guanine, thymine, thymidine,xanthine, xanthosine, xanthosine monophosphate, caffeine, allantoin,(2-hydroxyethyl)urea, N,N′-bis(hydroxymethyl)urea, pentaerythritolethoxylate, pentaerythritol propoxylate, pentaerythritolpropoxylate/ethoxylate, glycerol ethoxylate, glycerol propoxylate,trimethylolpropane ethoxylate, pentaerythritol, dipentaerythritol, crownether, 18-crown-6, 15-crown-5, 12-crown-4, and combinations thereof.

In some embodiments, the coating layer does not include one or more ofan iodine covalent-bonded contrast agent, a dye, an oil, and a lipid. Insome embodiments, the hydrophobic therapeutic agent is not enclosed inone or more of micelles and liposomes. In some embodiments, thehydrophobic therapeutic agent is not encapsulated in polymer particles.In some embodiments, the coating is free of one or more of micelles,liposomes, and polymer particles.

In one embodiment, the nonvascular body lumen is one of esophagus,airways, sinus, trachea, colon, biliary tract, urinary tract, prostate,urethral, ureteral, and other nonvascular lumens.

In one embodiment of the balloon catheter, the one or more water-solubleadditives promote a rapid release of the hydrophobic therapeutic agentfrom the balloon, and whereby the rapid release includes a residual drugamount of the hydrophobic therapeutic agent remaining on the balloonafter the balloon is inflated at the target site of the nonvascular bodylumen for an inflation period of from about 0.1 minutes to 10 minutesand subsequently removed from the nonvascular lumen.

In one embodiment of the balloon catheter, the ratio by weight of thehydrophobic therapeutic agent in the coating layer to the total weightof the one or more additives in the coating layer is about 0.05 to about20, about 0.1 to about 10, about 0.1 to about 5, about 0.5 to about 8,about 0.5 to about 3, about 2 to about 6, or about 0.05 or less, or lessthan, equal to, or greater than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,12, 13, 14, 15, 16, 17, 18, 19, or about 20 or more. In one embodimentof the balloon catheter, the ratio by weight of the hydrophobictherapeutic agent in the coating layer to the total weight of the one ormore water-soluble additives (e.g., a first and second water solubleadditive in the coating layer, or to the total weight of a first,second, and third water soluble additive) in the coating layer, is fromabout 0.05 to about 20, about 0.1 to about 10, about 0.1 to about 5,about 0.5 to about 8, about 0.5 to about 3, about 2 to about 6, or about0.05 or less, or less than, equal to, or greater than about 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or about 20 ormore.

In one embodiment of the balloon catheter, the initial drug load is from1 microgram to 20 micrograms of the hydrophobic therapeutic agent persquare millimeter of the balloon (i.e., per external surface area of theballoon), or about 2 to about 6 micrograms, or about 1 microgram orless, or less than, equal to, or greater than about 2, 3, 4, 5, 6, 7, 8,9, 10, 12, 14, 16, 18, or about 20 micrograms or more. The residual drugamount can be 70% or less of the initial drug load.

In one embodiment, the present invention relates to a method fortreating a stricture in a nonvascular body lumen, the method includingflushing the nonvascular body lumen with water, saline solution, or awater solution including at least one water soluble additive; insertinga balloon catheter to a target site in the stricture in the nonvascularbody lumen, the balloon catheter including a balloon and a coating layeroverlying external surfaces of the balloon. The coating layer includes aat least one water-soluble additive, and an initial drug load of ahydrophobic therapeutic agent; the hydrophobic therapeutic agent isselected from the group consisting of paclitaxel, paclitaxel analogues,rapamycin, rapamycin analogues, and combinations thereof; thewater-soluble additive is selected from the group consisting ofN-acetylglucosamine, N-octyl-D-gluconamide,N-Nonanoyl-N-methylglycamine, N-octanoyl-N-methyl glutamine C6-ceramide,dihydro-C6-ceramide, cerabroside, sphingomyelin, galaclocerebrosides,lactocerebrosides, N-acetyl-D-sphingosine, N-hexanoyl-D-sphingosine,N-octonoyl-D-sphingosine, N-Lauroyl-D-sphingosine,N-palmitoyl-D-sphingosine, N-oleoyl-D-sphingosine, PEG caprylic/capricdiglycerides, PEG8 caprylic/capric glycerides, PEG caprylate, PEG8caprylate, PEG caprate, PEG caproate, glyceryl monocaprylate, glycerylmonocaprate, glyceryl monocaproate, monolaurin, monocaprin,monocaprylin, monomyristin, monopalmitolein, monoolein, creatine,creatinine, agmatine, citrulline, guanidine, sucralose, aspartame,hypoxanthine, theobromine, theophylline, adenine, uracil, uridine,guanine, thymine, thymidine, xanthine, xanthosine, xanthosinemonophosphate, caffeine, allantoin, (2-hydroxyethyl)urea,N,N′-bis(hydroxymethyl) urea, pentaerythritol ethoxylate,pentaerythritol propoxylate, pentaerythritol propoxylate/ethoxylate,glycerol ethoxylate, glycerol propoxylate, trimethylolpropaneethoxylate, pentaerythritol, dipentaerythritol, crown ether, 18-crown-6,15-crown-5, 12-crown-4, and combinations thereof; inflating the balloonuntil the coating layer contacts walls of the stricture in thenonvascular body lumen at the target site for an inflation period;deflating the balloon after the inflation period, wherein the inflationperiod is from 0.1 minutes to 10 minutes; and withdrawing the ballooncatheter from the stricture in the nonvascular body lumen. The inflatedballoon catheter diameter can be such that the ratio of the balloondiameter to the nonvascular lumen diameter is about 1.01 to about 30, orabout 1.2 to about 25, or about 1.5 to about 20, or about 1.01 or less,or less than, equal to, or greater than about 1.1, 1.2, 1.3, 1.4, 1.5,1.6, 1.8, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 22, 24, 26,28, or about 30 or more.

In one embodiment of the method, the one or more water-soluble additivespromote rapid release of the hydrophobic therapeutic agent from theballoon at the target site during an inflation period.

In one embodiment of the method, the balloon has thereon a residual drugamount after the withdrawing. Any suitable residual drug amount canremain after the withdrawing, such as greater than, equal to, or lessthan about 90 wt %, 88, 86, 84, 82, 80, 78, 76, 74, 72, 70, 68, 66, 64,62, 60, 58, 56, 54, 52, 50, 48, 46, 44, 42, 40, 38, 36, 34, 32, 30, 28,26, 24, 22, 20, 18, 16, 14, 12, 10, 8, 6, 4, 3, 2, 1 wt %, or about 0 wt%.

In one embodiment of the method, the stricture in the nonvascular bodylumen is one of, urethral strictures, ureteral strictures, esophagealstrictures, sinus strictures, and biliary tract strictures.

In one embodiment of the method, the ratio by weight of the therapeuticagent in the coating layer to the total weight of the one or moreadditives in the coating layer is about 0.05 to about 20, about 0.1 toabout 10, about 0.1 to about 5, about 0.5 to about 8, about 0.5 to about3, about 2 to about 6, or about 0.05 or less, or less than, equal to, orgreater than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, or about 20 or more.

In one embodiment of the method, the initial drug load is from 1microgram to 20 micrograms of the hydrophobic therapeutic agent persquare millimeter of the balloon, or about 2 to about 6 micrograms, orabout 1 microgram or less, or less than, equal to, or greater than about2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or about 20 micrograms ormore. The residual drug amount can be 70% or less of the initial drugload.

In one embodiment, the present invention relates to a method fortreating at least one of a benign prostatic hyperplasia and prostatecancer, the method including flushing the prostate with water, salinesolution, or a water solution including at least one water solubleadditive; inserting a balloon catheter to a target site in the prostate,the balloon catheter including a balloon and a coating layer overlyingexternal surfaces of the balloon. The coating layer can include one ormore water-soluble additives, and an initial drug load of a hydrophobictherapeutic agent; the hydrophobic therapeutic agent is selected fromthe group consisting of paclitaxel, paclitaxel analogues, rapamycin,rapamycin analogues, and combinations thereof; the water-solubleadditive is selected from the group consisting of N-acetylglucosamine,N-octyl-D-gluconamide, N-nonanoyl-N-methylglycamine, N-octanoyl-N-methylglutamine, C6-ceramide, dihydro-C6-ceramide, cerabroside, sphingomyelin,galaclocerebrosides, lactocerebrosides, N-acetyl-D-sphingosine,N-hexanoyl-D-sphingosine, N-octonoyl-D-sphingosine,N-lauroyl-D-sphingosine, N-palmitoyl-D-sphingosine,N-oleoyl-D-sphingosine, PEG caprylic/capric diglycerides, PEG8caprylic/capric glycerides, PEG caprylate, PEG8 caprylate, PEG caprate,PEG caproate, glyceryl monocaprylate, glyceryl monocaprate, glycerylmonocaproate, monolaurin, monocaprin, monocaprylin, monomyristin,monopalmitolein, monoolein, creatine, creatinine, agmatine, citrulline,guanidine, sucralose, aspartame, hypoxanthine, theobromine,theophylline, adenine, uracil, uridine, guanine, thymine, thymidine,xanthine, xanthosine, xanthosine monophosphate, caffeine, allantoin,(2-hydroxyethyl)urea, N,N′-bis(hydroxymethyl)urea, pentaerythritolethoxylate, pentaerythritol propoxylate, pentaerythritolpropoxylate/ethoxylate, glycerol ethoxylate, glycerol propoxylate,trimethylolpropane ethoxylate, pentaerythritol, dipentaerythritol, crownether, 18-crown-6, 15-crown-5, 12-crown-4, and combinations thereof;inflating the balloon until the coating layer contacts walls of thebenign prostatic hyperplasia or prostate cancer at the target site foran inflation period: deflating the balloon after the inflation period,wherein the inflation period is from 0.1 minutes to 10 minutes; andwithdrawing the balloon catheter from the prostate. The inflated ballooncatheter diameter can be such that the ratio of the balloon diameter tothe nonvascular lumen diameter is about 1.01 to about 30, or about 1.2to about 25, or about 1.5 to about 20, or about 1.01 or less, or lessthan, equal to, or greater than about 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.8,2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, or about30 or more.

In one embodiment of the method, the one or more water-soluble additivespromote rapid release of the hydrophobic therapeutic agent from theballoon at the target site during an inflation period.

In one embodiment of the method, the balloon has thereon a residual drugamount after the withdrawing.

In one embodiment of the method, the ratio by weight of the hydrophobicagent in the coating layer to the total weight of the one or moreadditives in the coating layer is about 0.05 to about 20, about 0.1 toabout 10, about 0.1 to about 5, about 0.5 to about 8, about 0.5 to about3, about 2 to about 6, or about 0.05 or less, or less than, equal to, orgreater than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, or about 20 or more.

In one embodiment of the method, the initial drug load is from 1microgram to 20 micrograms of the hydrophobic therapeutic agent persquare millimeter of the balloon, or about 2 to about 6 micrograms, orabout 1 microgram or less, or less than, equal to, or greater than about2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or about 20 micrograms ormore. The residual drug amount can be 70% or less of the initial drugload.

In one embodiment, the present invention relates to a method fortreating a urethral stricture, the method including flushing theurethral stricture with water, saline solution, or a water solutionincluding at least one water soluble additive; inserting a ballooncatheter to a target site in the urethral stricture, the ballooncatheter including a balloon and a coating layer overlying externalsurfaces of the balloon, wherein the coating layer includes at least onewater-soluble additive, and an initial drug load of a hydrophobictherapeutic agent; the hydrophobic therapeutic agent is selected fromthe group consisting of paclitaxel, paclitaxel analogues, rapamycin,rapamycin analogues, and combinations thereof; the water-solubleadditive is selected from the group consisting of N-acetylglucosamine,N-octyl-D-gluconamide, N-nonanoyl-N-methylglycamine, N-octanoyl-N-methylglutamine, C6-ceramide, dihydro-C6-ceramide, cerabroside, sphingomyelin,galaclocerebrosides, lactocerebrosides, N-acetyl-D-sphingosine,N-hexanoyl-D-sphingosine, N-octonoyl-D-sphingosine,N-lauroyl-D-sphingosine, N-palmitoyl-D-sphingosine,N-oleoyl-D-sphingosine, PEG caprylic/capric diglycerides, PEG8caprylic/capric glycerides, PEG caprylate, PEG8 caprylate, PEG caprate,PEG caproate, glyceryl monocaprylate, glyceryl monocaprate, glycerylmonocaproate, monolaurin, monocaprin, monocaprylin, monomyristin,monopalmitolein, monoolein, creatine, creatinine, agmatine, citrulline,guanidine, sucralose, aspartame, hypoxanthine, theobromine,theophylline, adenine, uracil, uridine, guanine, thymine, thymidine,xanthine, xanthosine, xanthosine monophosphate, caffeine, allantoin,(2-hydroxyethyl)urea, N,N′-bis(hydroxymethyl)urea, pentaerythritolethoxylate, pentaerythritol propoxylate, pentaerythritolpropoxylate/ethoxylate, glycerol ethoxylate, glycerol propoxylate,trimethylolpropane ethoxylate, pentaerythritol, dipentaerythritol, crownether, 18-crown-6, 15-crown-5, 12-crown-4, and combinations thereof; andthe ratio by weight of the hydrophobic therapeutic agent in the coatinglayer to the total weight of the one or more water-soluble additives inthe coating layer is from about 0.05 to 20; inflating the balloon untilthe coating layer contacts walls of the urethral stricture at the targetsite for an inflation period; deflating the balloon after the inflationperiod, wherein the inflation period is from 0.1 minutes to 10 minutes;and withdrawing the balloon catheter from the urethral stricture. Theinflated balloon catheter diameter can be such that the ratio of theballoon diameter to the nonvascular lumen diameter is about 1.01 toabout 30, or about 1.2 to about 25, or about 1.5 to about 20, or about1.01 or less, or less than, equal to, or greater than about 1.1, 1.2,1.3, 1.4, 1.5, 1.6, 1.8, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20,22, 24, 26, 28, or about 30 or more.

In one embodiment, the one or more water-soluble additive promotes rapidrelease of the hydrophobic therapeutic agent from the balloon at thetarget site during an inflation period.

In one embodiment, the balloon has thereon a residual drug amount ofless than 70% of the initial drug load after the withdrawing.

In one embodiment of the method, the ratio by weight of the therapeuticagent in the coating layer to the total weight of the one or moreadditives in the coating layer is about 0.05 to about 20, about 0.1 toabout 10, about 0.1 to about 5, about 0.5 to about 8, about 0.5 to about3, about 2 to about 6, or about 0.05 or less, or less than, equal to, orgreater than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, or about 20 or more.

In one embodiment of the method, the initial drug load is from 1microgram to 20 micrograms of the hydrophobic therapeutic agent persquare millimeter of the balloon, or about 2 to about 6 micrograms, orabout 1 microgram or less, or less than, equal to, or greater than about2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or about 20 micrograms ormore. The residual drug amount can be 70% or less of the initial drugload.

In one embodiment, the present invention relates to a method fortreating an esophageal stricture, the method including flushing theesophageal stricture with water, saline solution or a water solutionincluding at least one water soluble additive; inserting a ballooncatheter to a target site in the esophageal stricture, the ballooncatheter including a balloon and a coating layer overlying externalsurfaces of the balloon, wherein the coating layer includes at least onewater-soluble second additive, and a hydrophobic therapeutic agent withan initial drug load of from 1 to 6 micrograms of the hydrophobictherapeutic agent per square millimeter of the balloon; the hydrophobictherapeutic agent is selected from the group consisting of paclitaxel,paclitaxel analogues, rapamycin, rapamycin analogues, and combinationsthereof; the water-soluble additive is selected from the groupconsisting of N-acetylglucosamine, N-octyl-D-gluconamide,N-nonanoyl-N-methylglycamine, N-octanoyl-N-methyl glutamine,C6-ceramide, dihydro-C6-ceramide, cerabroside, sphingomyelin,galaclocerebrosides, lactocerebrosides, N-acetyl-D-sphingosine,N-hexanoyl-D-sphingosine, N-octonoyl-D-sphingosine,N-lauroyl-D-sphingosine, N-palmitoyl-D-sphingosine,N-oleoyl-D-sphingosine, PEG caprylic/capric diglycerides, PEG8caprylic/capric glycerides, PEG caprylate, PEG8 caprylate, PEG caprate,PEG caproate, glyceryl monocaprylate, glyceryl monocaprate, glycerylmonocaproate, monolaurin, monocaprin, monocaprylin, monomyristin,monopalmitolein, monoolein, creatine, creatinine, agmatine, citrulline,guanidine, sucralose, aspartame, hypoxanthine, theobromine,theophylline, adenine, uracil, uridine, guanine, thymine, thymidine,xanthine, xanthosine, xanthosine monophosphate, caffeine, allantoin,(2-hydroxyethyl)urea, N,N′-bis(hydroxymethyl)urea, pentaerythritolethoxylate, pentaerythritol propoxylate, pentaerythritolpropoxylate/ethoxylate, glycerol ethoxylate, glycerol propoxylate,trimethylolpropane ethoxylate, pentaerythritol, dipentaerythritol, crownether, 18-crown-6, 15-crown-5, 12-crown-4, and combinations thereof; andthe ratio by weight of the hydrophobic therapeutic agent in the coatinglayer to the total weight of the one or more water-soluble additives inthe coating layer is from about 0.05 to 20; inflating the balloon untilthe coating layer contacts walls of the esophageal stricture at thetarget site for an inflation period; deflating the balloon after theinflation period, wherein the inflation period is from 0.1 minutes to 10minutes; and withdrawing the balloon catheter from the esophagealstricture. The inflated balloon catheter diameter can be such that theratio of the balloon diameter to the nonvascular lumen diameter is about1.01 to about 30, or about 1.2 to about 25, or about 1.5 to about 20, orabout 1.01 or less, or less than, equal to, or greater than about 1.1,1.2, 1.3, 1.4, 1.5, 1.6, 1.8, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16,18, 20, 22, 24, 26, 28, or about 30 or more.

In one embodiment, the one or more water-soluble additives promote rapidrelease of the hydrophobic therapeutic agent from the balloon at thetarget site during an inflation period.

In one embodiment, the balloon has thereon a residual drug amount ofless than 70% of the initial drug load after the withdrawing.

In one embodiment, the ratio by weight of the hydrophobic therapeuticagent in the coating layer to the total weight of the one or moreadditives in the coating layer is about 0.05 to about 20, about 0.1 toabout 10, about 0.1 to about 5, about 0.5 to about 8, about 0.5 to about3, about 2 to about 6, or about 0.05 or less, or less than, equal to, orgreater than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, or about 20 or more.

In one embodiment, the initial drug load is from 1 microgram to 20micrograms of the hydrophobic therapeutic agent per square millimeter ofthe balloon, or about 2 to about 6 micrograms, or about 1 microgram orless, or less than, equal to, or greater than about 2, 3, 4, 5, 6, 7, 8,9, 10, 12, 14, 16, 18, or about 20 micrograms or more. The residual drugamount can be 70% or less of the initial drug load.

In one embodiment, the present invention relates to a method fortreating a sinus stricture, the method including: flushing the sinusstricture with water, saline solution, or a water solution including atleast one water soluble additives; inserting a balloon catheter to atarget site in the sinus stricture, the balloon catheter including aballoon and a coating layer overlying external surfaces of the balloon,wherein the coating layer includes at least one water-soluble additive,and a hydrophobic therapeutic agent with an initial drug load of from 1to 6 micrograms of the hydrophobic therapeutic agent per squaremillimeter of the balloon; the hydrophobic therapeutic agent is selectedfrom the group consisting of budesonide, flunisolide, triamcinolone,beclomethasone, fluticasone, mometasone, mometasone furoate,dexamethasone, hydrocortisone, methylprednisolone, prednisone,cortisone, betamethasone, triamcinolone acetonide, and combinationsthereof; the water-soluble additive is selected from the groupconsisting of N-acetylglucosamine, N-octyl-D-gluconamide,N-nonanoyl-N-methylglycamine, N-octanoyl-N-methyl glutamine,C6-ceramide, dihydro-C6-ceramide, cerabroside, sphingomyelin,galaclocerebrosides, lactocerebrosides, N-acetyl-D-sphingosine,N-hexanoyl-D-sphingosine, N-octonoyl-D-sphingosine,N-lauroyl-D-sphingosine, N-palmitoyl-D-sphingosine,N-oleoyl-D-sphingosine, PEG caprylic/capric diglycerides, PEG8caprylic/capric glycerides, PEG caprylate, PEG8 caprylate, PEG caprate,PEG caproate, glyceryl monocaprylate, glyceryl monocaprate, glycerylmonocaproate, monolaurin, monocaprin, monocaprylin, monomyristin,monopalmitolein, monoolein, creatine, creatinine, agmatine, citrulline,guanidine, sucralose, aspartame, hypoxanthine, theobromine,theophylline, adenine, uracil, uridine, guanine, thymine, thymidine,xanthine, xanthosine, xanthosine monophosphate, caffeine, allantoin,(2-hydroxyethyl)urea, N,N′-bis(hydroxymethyl)urea, pentaerythritolethoxylate, pentaerythritol propoxylate, pentaerythritolpropoxylate/ethoxylate, glycerol ethoxylate, glycerol propoxylate,trimethylolpropane ethoxylate, pentaerythritol, dipentaerythritol, crownether, 18-crown-6, 15-crown-5, 12-crown-4, and combinations thereof; andthe ratio by weight of the hydrophobic therapeutic agent in the coatinglayer to the total weight of the one or more water-soluble additives inthe coating layer is from about 0.05 to 20; inflating the balloon untilthe coating layer contacts walls of the sinus stricture at the targetsite for an inflation period; deflating the balloon after the inflationperiod, wherein the inflation period is from 0.1 minutes to 10 minutes;and withdrawing the balloon catheter from the sinus stricture.

In various embodiments, during inflation of the balloon in a body lumen(e.g., during performance of a method of the present invention), theinflated balloon diameter of the catheter can be such that the ratio ofthe inflated balloon diameter to the nonvascular lumen diameter (i.e.,the undilated body lumen) is any suitable ratio, such as about 1.01 toabout 30, or about 1.2 to about 25, or about 1.5 to about 20, or about1.01 or less, or less than, equal to, or greater than about 1.1, 1.2,1.3, 1.4, 1.5, 1.6, 1.8, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20,22, 24, 26, 28, or about 30 or more. In various embodiments, the ballooncatheter can be sufficient such that at a predetermined pressure (e.g.,the nominal pressure) the balloon can have any suitable ratio (e.g.,nominal ratio) of actual inflated balloon catheter diameter (e.g., thenominal inflated diameter, which may appear on a label associated withthe catheter) to nonvascular lumen diameter; for example, at a pressureof about 3 atm (304 kPa) to about 30 atm (3040 kPa) (e.g., about 3 atmor less, or less than, equal to, or more than about 4 atm, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 24, 26, 28, or about30 atm or more) the size of the inflated balloon catheter can be suchthat the ratio of the inflated balloon diameter to the nonvascular lumendiameter (i.e., the undilated body lumen) is any suitable ratio, such asabout 1.01 to about 30, or about 1.2 to about 25, or about 1.2 to about15, or about 1.5 to about 20, or about 1.01 or less, or less than, equalto, or greater than about 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.8, 2, 3, 4, 5,6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, or about 30 or more.In various embodiments, the balloon catheter can have a ratio of nominalinflated balloon catheter diameter (e.g., the nominal inflated diameterthat can appear on a label associated with the catheter) to undilatednonvascular lumen diameter of about 1.01 to about 30, or about 1.2 toabout 25, or about 1.2 to about 15, or about 1.5 to about 20, or about1.01 or less, or less than, equal to, or greater than about 1.1, 1.2,1.3, 1.4, 1.5, 1.6, 1.8, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20,22, 24, 26, 28, or about 30 or more.

In one embodiment, the one or more water-soluble additives promote rapidrelease of the hydrophobic therapeutic agent from the balloon at thetarget site during an inflation period.

In one embodiment, the balloon has thereon a residual drug amount ofless than 70% of the initial drug load after the withdrawing.

In one embodiment, the ratio by weight of the therapeutic agent in thecoating layer to the total weight of the one or more additives is about0.05 to about 20, about 0.1 to about 10, about 0.1 to about 5, about 0.5to about 8, about 0.5 to about 3, about 2 to about 6, or about 0.05 orless, or less than, equal to, or greater than about 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or about 20 or more.

In one embodiment, the initial drug load is from 1 microgram to 20micrograms of the hydrophobic therapeutic agent per square millimeter ofthe balloon, or about 2 to about 6 micrograms, or about 1 microgram orless, or less than, equal to, or greater than about 2, 3, 4, 5, 6, 7, 8,9, 10, 12, 14, 16, 18, or about 20 micrograms or more. The residual drugamount can be 70% or less of the initial drug load.

Additive.

The additive of embodiments of the present invention has two parts. Onepart is hydrophilic and the other part is a drug affinity part. The drugaffinity part is a hydrophobic part and/or has an affinity to thetherapeutic agent by hydrogen bonding and/or van der Waals interactions.The drug affinity part of the additive may bind the lipophilic drug,such as rapamycin or paclitaxel. The hydrophilic portion acceleratesdiffusion and increases permeation of the drug into tissue. It mayfacilitate rapid movement of drug off the medical device duringdeployment at the target site by preventing hydrophobic drug moleculesfrom clumping to each other and to the device, increasing drugsolubility in interstitial spaces, and/or accelerating drug lumenthrough polar head groups to the lipid bilayer of cell membranes oftarget tissues. The additives of embodiments of the present inventionhave two parts that function together to facilitate rapid release ofdrug off the device surface and uptake by target tissue duringdeployment (by accelerating drug contact with tissues for which drug hashigh affinity) while preventing the premature release of drug from thedevice surface prior to device deployment at the target site.

In embodiments of the present invention, the therapeutic agent israpidly released after the medical device is brought into contact withtissue and is readily absorbed. For example, certain embodiments ofdevices of the present invention include drug coated balloon cathetersthat deliver a lipophilic anti-proliferative pharmaceutical (such aspaclitaxel or rapamycin) to nonvascular tissue through brief, directpressure contact at high drug concentration during balloon nonvascularbody balloon dilation. The lipophilic drug, for example, is retained intarget tissue at the delivery site, where it inhibits hyperplasia andrestenosis yet allows epithelization. In these embodiments, coatingformulations of the present invention not only facilitate rapid releaseof drug from the balloon surface and transfer of drug into targettissues during deployment, but also prevent drug from diffusing awayfrom the device during transit through tortuous anatomy prior toreaching the target site and from exploding off the device during theinitial phase of balloon inflation, before the drug coating is pressedinto direct contact with the surface of the body lumen. The additiveaccording to certain embodiments has a drug affinity part and ahydrophilic part. The drug affinity part is a hydrophobic part and/orhas an affinity to the therapeutic agent by hydrogen bonding and/or vander Waals interactions. The drug affinity part may include aliphatic andaromatic organic hydrocarbon compounds, such as benzene, toluene, andalkanes, among others. These parts are not water soluble. They may bindboth hydrophobic drug, with which they share structural similarities,and lipids of cell membranes. They have no covalently bonded iodine. Thedrug affinity part may include functional groups that can form hydrogenbonds with drug and with itself. The hydrophilic part may includehydroxyl groups, amine groups, amide groups, carbonyl groups, carboxylicacid and anhydrides, ethyl oxide, ethyl glycol, polyethylene glycol,ascorbic acid, amino acid, amino alcohol, glucose, sucrose, sorbitan,glycerol, polyalcohol, phosphates, sulfates, organic salts and theirsubstituted molecules, among others. One or more hydroxyl, carboxyl,acid, amide or amine groups, for example, may be advantageous since theyeasily displace water molecules that are hydrogen-bound to polar headgroups and surface proteins of cell membranes and may function to removethis barrier between hydrophobic drug and cell membrane lipid. Theseparts can dissolve in water and polar solvents. In various embodiments,these additives do not include oils, lipids, or polymers. In variousembodiments, the therapeutic agent is not enclosed in micelles orliposomes or encapsulated in polymer particles. The additive ofembodiments of the present invention has components to both bind drugand facilitate its rapid movement off the medical device duringdeployment and into target tissues.

The additives in embodiments of the present invention are surfactantsand chemical compounds with one or more hydroxyl, amino, carbonyl,carboxyl, acid, amide or ester moieties. The surfactants include ionic,nonionic, aliphatic, and aromatic surfactants. The chemical compoundswith one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide orester moieties are chosen from amino alcohols, hydroxyl carboxylic acidand anhydrides, ethyl oxide, ethyl glycols, amino acids, peptides,proteins, sugars, glucose, sucrose, sorbitan, glycerol, polyalcohol,phosphates, sulfates, organic acids, esters, salts, vitamins, and theirsubstituted molecules.

As is well known in the art, the terms “hydrophilic” and “hydrophobic”are relative terms. To function as an additive in exemplary embodimentsof the present invention, the compound includes polar or chargedhydrophilic moieties as well as non-polar hydrophobic (lipophilic)moieties.

An empirical parameter commonly used in medicinal chemistry tocharacterize the relative hydrophilicity and hydrophobicity ofpharmaceutical compounds is the partition coefficient, P, the ratio ofconcentrations of unionized compound in the two phases of a mixture oftwo immiscible solvents, usually octanol and water, such thatP=([solute]octanol/[solute]water). Compounds with higher log Ps are morehydrophobic, while compounds with lower log Ps are more hydrophilic.Lipinski's rule suggests that pharmaceutical compounds having log P<5are typically more membrane permeable. For purposes of certainembodiments of the present invention, for example, the additive has logP less than log P of the drug to be formulated (as an example, log P ofpaclitaxel is 7.4). A greater log P difference between the drug and theadditive can facilitate phase separation of drug. For example, if log Pof the additive is much lower than log P of the drug, the additive mayaccelerate the release of drug in an aqueous environment from thesurface of a device to which drug might otherwise tightly adhere,thereby accelerating drug delivery to tissue during brief deployment atthe site of intervention. In certain embodiments of the presentinvention, log P of the additive is negative. In other embodiments, logP of the additive is less than log P of the drug. While a compound'soctanol-water partition coefficient P or log P is useful as ameasurement of relative hydrophilicity and hydrophobicity, it is merelya rough guide that may be useful in defining suitable additives for usein embodiments of the present invention.

Suitable additives that can be used in embodiments of the presentinvention include, without limitation, organic and inorganicpharmaceutical recipients, natural products and derivatives thereof(such as sugars, vitamins, amino acids, peptides, proteins, and fattyacids), low molecular weight oligomers, surfactants (anionic, cationic,non-ionic, and ionic), and mixtures thereof. The following detailed listof additives useful in the present invention is provided for exemplarypurposes only and is not intended to be comprehensive. Many otheradditives may be useful for purposes of the present invention.

Surfactants.

The surfactant can be any surfactant suitable for use in pharmaceuticalcompositions. Such surfactants can be anionic, cationic, zwitterionic ornon-ionic. Mixtures of surfactants are also within the scope of theinvention, as are combinations of surfactant and other additives.Surfactants often have one or more long aliphatic chains such as fattyacids that may insert directly into lipid bilayers of cell membranes toform part of the lipid structure, while other components of thesurfactants loosen the lipid structure and enhance drug penetration andabsorption. The contrast agent iopromide does not have these properties.

An empirical parameter commonly used to characterize the relativehydrophilicity and hydrophobicity of surfactants is thehydrophilic-lipophilic balance (“HLB” value). Surfactants with lower HLBvalues are more hydrophobic, and have greater solubility in oils, whilesurfactants with higher HLB values are more hydrophilic, and havegreater solubility in aqueous solutions. Using HLB values as a roughguide, hydrophilic surfactants are generally considered to be thosecompounds having an HLB value greater than about 10, as well as anionic,cationic, or zwitterionic compounds for which the HLB scale is notgenerally applicable. Similarly, hydrophobic surfactants are compoundshaving an HLB value less than about 10. In certain embodiments of thepresent invention, a higher HLB value is utilized, since increasedhydrophilicity may facilitate release of hydrophobic drug from thesurface of the device. In one embodiment, the HLB of the surfactantadditive is higher than 10. In another embodiment, the additive HLB ishigher than 14. Alternatively, surfactants having lower HLB may beutilized to prevent drug loss prior to device deployment at the targetsite, for example in a top coat over a drug layer that has a veryhydrophilic additive.

It should be understood that the HLB value of a surfactant is merely arough guide generally used to enable formulation of industrial,pharmaceutical and cosmetic emulsions, for example. For many importantsurfactants, including several polyethoxylated surfactants, it has beenreported that HLB values can differ by as much as about 8 HLB units,depending upon the empirical method chosen to determine the HLB value(Schott, J. Pharm. Sciences, 79(1), 87-88 (1990)). Keeping theseinherent difficulties in mind, and using HLB values as a guide,surfactants may be identified that have suitable hydrophilicity orhydrophobicity for use in embodiments of the present invention, asdescribed herein.

PEG-Fatty Acids and PEG-Fatty Acid Mono and Diesters.

Although polyethylene glycol (PEG) itself does not function as asurfactant, a variety of PEG-fatty acid esters have useful surfactantproperties. Among the PEG-fatty acid monoesters, esters of lauric acid,oleic acid, and stearic acid are most useful in embodiments of thepresent invention. Examples of hydrophilic surfactants include PEG-8laurate, PEG-8 oleate, PEG-8 stearate, PEG-9 oleate, PEG-10 laurate,PEG-10 oleate, PEG-12 laurate, PEG-12 oleate, PEG-15 oleate, PEG-20laurate and PEG-20 oleate. The HLB values are in the range of 4-20.

Polyethylene glycol fatty acid diesters are also suitable for use assurfactants in the compositions of embodiments of the present invention.Hydrophilic surfactants include PEG-20 dilaurate, PEG-20 dioleate,PEG-20 distearate, PEG-32 dilaurate and PEG-32 dioleate. The HLB valuesare in the range of 5-15.

In general, mixtures of surfactants are also useful in embodiments ofthe present invention, including mixtures of two or more commercialsurfactants as well as mixtures of surfactants with another additive oradditives. Several PEG-fatty acid esters are marketed commercially asmixtures or mono- and di-esters.

Polyethylene Glycol Glycerol Fatty Acid Esters.

Hydrophilic surfactants are PEG-20 glyceryl laurate, PEG-30 glyceryllaurate, PEG-40 glyceryl laurate, PEG-20 glyceryl oleate, and PEG-30glyceryl oleate.

Alcohol-Oil Transesterification Products.

A large number of surfactants of different degrees of hydrophobicity orhydrophilicity can be prepared by reaction of alcohols or polyalcoholwith a variety of natural and/or hydrogenated oils. Most commonly, theoils used are castor oil or hydrogenated castor oil, or an ediblevegetable oil such as corn oil, olive oil, peanut oil, palm kernel oil,apricot kernel oil, or almond oil. Alcohols include glycerol, propyleneglycol, ethylene glycol, polyethylene glycol, sorbitol, andpentaerythritol. Among these alcohol-oil transesterified surfactants,hydrophilic surfactants are PEG-35 castor oil (Incrocas-35), PEG-40hydrogenated castor oil (Cremophor RH 40), PEG-25 trioleate (TAGAT.®TO), PEG-60 corn glycerides (Crovol M70), PEG-60 almond oil (CrovolA70), PEG-40 palm kernel oil (Crovol PK70), PEG-50 castor oil (EmalexC-50), PEG-50 hydrogenated castor oil (Emalex HC-50), PEG-8caprylic/capric glycerides (Labrasol), and PEG-6 caprylic/capricglycerides (Softigen 767). For example, hydrophobic surfactants in thisclass include PEG-5 hydrogenated castor oil, PEG-7 hydrogenated castoroil, PEG-9 hydrogenated castor oil, PEG-6 corn oil (Labrafil® M 2125CS), PEG-6 almond oil (Labrafil® M 1966 CS), PEG-6 apricot kernel oil(Labrafil® M 1944 CS), PEG-6 olive oil (Labrafil® M 1980 CS), PEG-6peanut oil (Labrafil® M 1969 CS), PEG-6 hydrogenated palm kernel oil(Labrafil® M BS), PEG-6 palm kernel oil (Labrafil® M 2130 CS), PEG-6triolein (Labrafil®b M 2735 CS), PEG-8 corn oil (Labrafil® WL 2609 BS),PEG-20 corn glycerides (Crovol M40), and PEG-20 almond glycerides(Crovol A40).

Polyglyceryl Fatty Acids.

Polyglycerol esters of fatty acids are also suitable surfactants for usein embodiments of the present invention. Among the polyglyceryl fattyacid esters, hydrophobic surfactants include polyglyceryl oleate (PlurolOleique), polyglyceryl-2 dioleate (Nikkol DGDO), polyglyceryl-10trioleate, polyglyceryl stearate, polyglyceryl laurate, polyglycerylmyristate, polyglyceryl palmitate, and polyglyceryl linoleate.Hydrophilic surfactants include polyglyceryl-10 laurate (Nikkol Decaglyn1-L), polyglyceryl-10 oleate (Nikkol Decaglyn 1-0), and polyglyceryl-10mono, dioleate (CaproI® PEG 860), polyglyceryl-10 stearate,polyglyceryl-10 laurate, polyglyceryl-myristate, polyglyceryl-10palmitate, polyglyceryl-10 linoleate, polyglyceryl-6 stearate,polyglyceryl-6 laurate, polyglyceryl-6 myristate, polyglyceryl-6palmitate, and polyglyceryl-6 linoleate. Polyglyceryl polyricinoleates(Polymuls) are also surfactants.

Propylene Glycol Fatty Acid Esters.

Esters of propylene glycol and fatty acids are suitable surfactants foruse in embodiments of the present invention. In this surfactant class,hydrophobic surfactants include propylene glycol monolaurate(Lauroglycol FCC), propylene glycol ricinoleate (Propymuls), propyleneglycol monooleate (Myverol P-06), propylene glycol dicaprylate/dicaprate(Captex® 200), and propylene glycol dioctanoate (Captex® 800).

Sterol and Sterol Derivatives.

Sterols and derivatives of sterols are suitable surfactants for use inembodiments of the present invention. Derivatives include thepolyethylene glycol derivatives. A surfactant in this class is PEG-24cholesterol ether (Solulan C-24).

Polyethylene Glycol Sorbitan Fatty Acid Esters.

A variety of PEG-sorbitan fatty acid esters are available and aresuitable for use as surfactants in embodiments of the present invention.Among the PEG-sorbitan fatty acid esters, surfactants include PEG-20sorbitan monolaurate (Tween-20), PEG-20 sorbitan monopalmitate(Tween-40), PEG-20 sorbitan monostearate (Tween-60). PEG-20 sorbitanmonooleate (Tween-80). In some embodiments, laurate esters are utilizedbecause they have a short lipid chain compared with oleate esters,increasing drug absorption.

Polyethylene Glycol Alkyl Ethers.

Ethers of polyethylene glycol and alkyl alcohols are suitablesurfactants for use in embodiments of the present invention. Ethersinclude PEG-3 oleyl ether (Volpo 3) and PEG-4 lauryl ether (Brij 30).

Sugar and its Derivatives.

Sugar derivatives are suitable surfactants for use in embodiments of thepresent invention. Surfactants in this class include sucrosemonopalmitate, sucrose monolaurate, decanoyl-N-methylglucamide,n-decyl-β-D-glucopyranoside, n-decyl-β-D-maltopyranoside,n-dodecyl-β-D-glucopyranoside, n-dodecyl-β-D-maltoside,heptanoyl-N-methylglucamide, n-heptyl-β-D-glucopyranoside,n-heptyl-β-D-thioglucoside, n-hexyl-β-D-glucopyranoside,nonanoyl-N-methylglucamide, n-nonyl-β-D-glucopyranoside,octanoyl-N-methylglucamide, n-octyl-β-D-glucopyranoside, andoctyl-O-D-thioglucopyranoside.

Polyethylene Glycol Alkyl Phenols.

Several PEG-alkyl phenol surfactants are available, such as PEG-10-100nonyl phenol and PEG-15-100 octyl phenol ether, Tyloxapol, octoxynol,nonoxynol, and are suitable for use in embodiments of the presentinvention.

Polyoxyethylene-Polyoxypropylene (POE-POP) Block Copolymers.

The POE-POP block copolymers are a unique class of polymericsurfactants. The unique structure of the surfactants, with hydrophilicPOE and hydrophobic POP moieties in well-defined ratios and positions,provides a wide variety of surfactants suitable for use in embodimentsof the present invention. These surfactants are available under varioustrade names, including Synperonic PE series (ICI); Pluronic® series(BASF), Emkalyx, Lutrol (BASF), Supronic, Monolan, Pluracare, andPlurodac. The generic term for these polymers is “poloxamer” (CAS9003-11-6). These polymers have the formula:HO(C₂H₄O)_(a)(C₃H₆O)_(b)(C₂H₄O)_(a)H where “a” and “b” denote the numberof polyoxyethylene and polyoxypropylene units, respectively.

Hydrophilic surfactants of this class include Poloxamers 108, 188, 217,238, 288, 338, and 407. Hydrophobic surfactants in this class includePoloxamers 124, 182, 183, 212, 331, and 335.

Sorbitan Fatty Acid Esters.

Sorbitan esters of fatty acids are suitable surfactants for use inembodiments of the present invention. Among these esters, hydrophobicsurfactants include sorbitan monolaurate (Arlacel 20), sorbitanmonopalmitate (Span-40), and sorbitan monooleate (Span-80), sorbitanmonostearate.

The sorbitan monopalmitate, an amphiphilic derivative of Vitamin C(which has Vitamin C activity), can serve two important functions insolubilization systems. First, it possesses effective polar groups thatcan modulate the microenvironment. These polar groups are the samegroups that make vitamin C itself (ascorbic acid) one of the mostwater-soluble organic solid compounds available: ascorbic acid issoluble to about 30 wt/wt % in water (very close to the solubility ofsodium chloride, for example). And second, when the pH increases so asto convert a fraction of the ascorbyl palmitate to a more soluble salt,such as sodium ascorbyl palmitate.

Ionic Surfactants.

Ionic surfactants, including cationic, anionic and zwitterionicsurfactants, are suitable hydrophilic surfactants for use in embodimentsof the present invention. Ionic surfactants include quaternary ammoniumsalts, fatty acid salts and bile salts. Specifically, ionic surfactantsinclude benzalkonium chloride, benzethonium chloride, cetylpyridiniumchloride, docecyl trimethyl ammonium bromide, sodium docecylsulfates,dialkyl methylbenzyl ammonium chloride, edrophonium chloride, domiphenbromide, dialkylester of sodium sulfonsuccinic acid, sodium dioctylsulfosuccinate, sodium cholate, and sodium taurocholate. They can bedissolved in both organic solvents (such as ethanol, acetone, andtoluene) and water. This is especially useful for medical devicecoatings because it simplifies the preparation and coating process andhas good adhesive properties. Water insoluble drugs are commonlydissolved in organic solvents.

Some of the surfactants described herein are very stable under heating.They survive an ethylene oxide sterilization process. They do not reactwith drugs such as paclitaxel or rapamycin under the sterilizationprocess. The hydroxyl, ester, amide groups are utilized because they areunlikely to react with drug, while amine and acid groups often do reactwith paclitaxel or rapamycin during sterilization. Furthermore,surfactant additives improve the integrity and quality of the coatinglayer, so that particles do not fall off during handling. When thesurfactants described herein are formulated with paclitaxel,experimentally it protects drug from premature release during the devicedelivery process while facilitating rapid release and elution ofpaclitaxel during a very brief deployment time of 0.2 to 10 minutes atthe target site. Drug absorption by tissues at the target site isunexpectedly high experimentally.

Chemical Compounds with One or More Hydroxyl, Amino, Carbonyl, Carboxyl,Acid. Amide or Ester Moieties.

The chemical compounds with one or more hydroxyl, amino, carbonyl,carboxyl, acid, amide or ester moieties include creatine, creatinine,agmatine, citrulline, guanidine, sucralose, aspartame, hypoxanthine,theobromine, theophylline, adenine, uracil, uridine, guanine, thymine,thymidine, xanthine, xanthosine, xanthosine monophosphate, caffeine,allantoin, (2-hydroxyethyl)urea, N,N′-bis(hydroxymethyl)urea,pentaerythritol ethoxylate, pentaerythritol propoxylate, pentaerythritolpropoxylate/ethoxylate, glycerol ethoxylate, glycerol propoxylate,trimethylolpropane ethoxylate, pentaerythritol, dipentaerythritol, crownether, 18-crown-6, 15-crown-5, 12-crown-4, N-acetylglucosamine,N-octyl-D-gluconamide, C6-ceramide, dihydro-C6-ceramide, cerabroside,sphingomyelin, galaclocerebrosides, lactocerebrosides,N-acetyl-D-sphingosine, N-hexanoyl-D-sphingosine,N-octonoyl-D-sphingosine, N-Lauroyl-D-sphingosine,N-palmitoyl-D-sphingosine, N-oleoyl-D-sphingosine, PEG caprylic/capricdiglycerides, PEG8 caprylic/capric glycerides, PEG caprylate, PEG8caprylate (e.g., Labrasol®), PEG caprate, PEG caproate, glycerylmonocaprylate, glyceryl monocaprate, glyceryl monocaproate, monolaurin,monocaprin, monocaprylin, monomyristin, monopalmitolein, and monoolein.

The chemical compounds with one or more hydroxyl, amino, carbonyl,carboxyl, acid, amide or ester moieties include amino alcohols, hydroxylcarboxylic acid, ester, and anhydrides, hydroxyl ketone, hydroxyllactone, hydroxyl ester, sugar phosphate, sugar sulfate, ethyl oxide,ethyl glycols, amino acids, peptides, proteins, sorbitan, glycerol,polyalcohol, phosphates, sulfates, organic acids, esters, salts,vitamins, combinations of amino alcohols and organic acids, and theirsubstituted molecules. Hydrophilic chemical compounds with one or morehydroxyl, amino, carbonyl, carboxyl, acid, amide or ester moietieshaving a molecular weight less than 5,000-10,000 are utilized in certainembodiments. In other embodiments, molecular weight of the additive withone or more hydroxyl, amino, carbonyl, carboxyl, acid, amide, or estermoieties is less than 1000-5,000, or less than 750-1,000, or less than750. In these embodiments, the molecular weight of the additive is to beless than that of the drug to be delivered. Further, the molecularweight of the additive is to be higher than 80 since molecules withmolecular weight less than 80 very easily evaporate and do not stay inthe coating of a medical device. Small molecules can diffuse quickly.They can release themselves easily from the delivery balloon,accelerating release of drug, and they can diffuse away from drug whenthe drug binds tissue of the body lumens.

In certain embodiments, additives with more than four hydroxyl groupsare utilized, for example in the case of a high molecular weightadditive. Large molecules diffuse slowly. If the molecular weight of theadditive or the chemical compound is high, for example if the molecularweight is above 800, above 1000, above 1200, above 1500, or above 2000;large molecules may elute off of the surface of the medical device tooslowly to release drug under 2 minutes. If these large molecules containmore than four hydroxyl groups they have increased hydrophilicproperties, which is necessary for relatively large molecules to releasedrug quickly. The increased hydrophilicity helps elute the coating offthe balloon, accelerates release of drug, and improves or facilitatesdrug movement through water barrier and polar head groups of lipidbilayers to penetrate tissues. In one embodiment, the hydroxyl group isutilized as the hydrophilic moiety because it is unlikely to react withwater insoluble drug, such as paclitaxel or rapamycin. In someembodiments, the chemical compound having more than four hydroxyl groupshas a melting point of 120° C. or less. In some embodiments, thechemical compound having more than four hydroxyl groups has threeadjacent hydroxyl groups that in stereo configuration are all on oneside of the molecule. For example, sorbitol and xylitol have threeadjacent hydroxyl groups that in stereo configuration are all on oneside of the molecule, while galactitol does not. The difference impactsthe physical properties of the isomers such as the melting temperature.The stereo configuration of the three adjacent hydroxyl groups mayenhance drug binding. This will lead to improved compatibility of thewater insoluble drug and hydrophilic additive, and improved tissueuptake and absorption of drug.

Some of the chemical compounds with one or more hydroxyl, amine,carbonyl, carboxyl, or ester moieties described herein are very stableunder heating. They survive an ethylene oxide sterilization process anddo not react with the water insoluble drug paclitaxel or rapamycinduring sterilization. L-ascorbic acid and its salt and diethanolamine,on the other hand, do not necessarily survive such a sterilizationprocess, and they react with paclitaxel. A different sterilizationmethod is therefore utilized for L-ascorbic acid and diethanolamine. Forexample, hydroxyl, ester, and amide groups are utilized because they areunlikely to react with therapeutic agents such as paclitaxel orrapamycin. Sometimes, amine and acid groups do react with paclitaxel,for example, experimentally, benzoic acid, gentisic acid,diethanolamine, and ascorbic acid were not stable under ethylene oxidesterilization, heating, and aging process and reacted with paclitaxel.When the chemical compounds described herein are formulated withpaclitaxel, a top coat layer may be advantageous in order to preventpremature drug loss during the device delivery process before deploymentat the target site, since hydrophilic small molecules sometimes releasedrug too easily. The chemical compounds herein rapidly elute drug offthe balloon during deployment at the target site. Surprisingly, eventhough some drug is lost during transit of the device to the target sitewhen the coating contains these additives, experimentally drugabsorption by tissue is unexpectedly high after only 0.2-10 minutes ofdeployment, for example, with the additive hydroxyl lactones such asribonic acid lactone and gluconolactone.

Fat-Soluble Vitamins and Salts Thereof.

Vitamins A, D, E and K in many of their various forms and provitaminforms are considered as fat-soluble vitamins and in addition to these anumber of other vitamins and vitamin sources or close relatives are alsofat-soluble and have polar groups, and relatively high octanol-waterpartition coefficients. Clearly, the general class of such compounds hasa history of safe use and high benefit to risk ratio, making them usefulas additives in embodiments of the present invention.

The following examples of fat-soluble vitamin derivatives and/or sourcesare also useful as additives: Alpha-tocopherol, beta-tocopherol,gamma-tocopherol, delta-tocopherol, tocopherol acetate, ergosterol,1-alpha-hydroxycholecal-ciferol, vitamin D2, vitamin D3, alpha-carotene,beta-carotene, gamma-carotene, vitamin A, fursultiamine,methylolriboflavin, octotiamine, prosultiamine, riboflavine, vintiamol,dihydrovitamin K1, menadiol diacetate, menadiol dibutyrate, menadioldisulfate, menadiol, vitamin K1, vitamin K1 oxide, vitamins K2, andvitamin K—S(II). Folic acid is also of this type, and although it iswater-soluble at physiological pH, it can be formulated in the free acidform. Other derivatives of fat-soluble vitamins useful in embodiments ofthe present invention may easily be obtained via well known chemicalreactions with hydrophilic molecules.

Water-Soluble Vitamins and their Amphiphilic Derivatives.

Vitamins B, C, U, pantothenic acid, folic acid, and some of themenadione-related vitamins/provitamins in many of their various formsare considered water-soluble vitamins. These may also be conjugated orcomplexed with hydrophobic moieties or multivalent ions into amphiphilicforms having relatively high octanol-water partition coefficients andpolar groups. Again, such compounds can be of low toxicity and highbenefit to risk ratio, making them useful as additives in embodiments ofthe present invention. Salts of these can also be useful as additives inthe present invention. Examples of water-soluble vitamins andderivatives include, without limitation, acetiamine, benfotiamine,pantothenic acid, cetotiamine, cyclothiamine, dexpanthenol, niacinamide,nicotinic acid, pyridoxal 5-phosphate, nicotinamide ascorbate,riboflavin, riboflavin phosphate, thiamine, folic acid, menadioldiphosphate, menadione sodium bisulfite, menadoxime, vitamin B12,vitamin K5, vitamin K6, vitamin K6, and vitamin U. Also, as mentionedabove, folic acid is, over a wide pH range including physiological pH,water-soluble, as a salt.

Compounds in which an amino or other basic group is present can easilybe modified by simple acid-base reaction with a hydrophobicgroup-containing acid such as a fatty acid (especially lauric, oleic,myristic, palmitic, stearic, or 2-ethylhexanoic acid), low-solubilityamino acid, benzoic acid, salicylic acid, or an acidic fat-solublevitamin (such as riboflavin). Other compounds might be obtained byreacting such an acid with another group on the vitamin such as ahydroxyl group to form a linkage such as an ester linkage, etc.Derivatives of a water-soluble vitamin containing an acidic group can begenerated in reactions with a hydrophobic group-containing reactant suchas stearylamine or riboflavine, for example, to create a compound thatis useful in embodiments of the present invention. The linkage of apalmitate chain to vitamin C yields ascorbyl palmitate.

Amino Acids and their Salts.

Alanine, arginine, asparagines, aspartic acid, cysteine, cystine,glutamic acid, glutamine, glycine, histidine, proline, isoleucine,leucine, lysine, methionine, phenylalanine, serine, threonine,tryptophan, tyrosine, valine, and derivatives thereof are other usefuladditives in embodiments of the invention.

Certain amino acids, in their zwitterionic form and/or in a salt formwith a monovalent or multivalent ion, have polar groups, relatively highoctanol-water partition coefficients, and are useful in embodiments ofthe present invention. In the context of the present disclosure we take“low-solubility amino acid” to mean an amino acid which has solubilityin unbuffered water of less than about 4% (40 mg/ml). These includeCystine, tyrosine, tryptophan, leucine, isoleucine, phenylalanine,asparagine, aspartic acid, glutamic acid, and methionine.

Amino acid dimers, sugar-conjugates, and other derivatives are alsouseful. Through simple reactions well known in the art hydrophilicmolecules may be joined to hydrophobic amino acids, or hydrophobicmolecules to hydrophilic amino acids, to make additional additivesuseful in embodiments of the present invention.

Catecholamines, such as dopamine, levodopa, carbidopa, and DOPA, arealso useful as additives.

Oligopeptides. Peptides and Proteins.

Oligopeptides and peptides are useful as additives, since hydrophobicand hydrophilic amino acids may be easily coupled and various sequencesof amino acids may be tested to maximally facilitate permeation oftissue by drug.

Proteins are also useful as additives in embodiments of the presentinvention. Serum albumin, for example, is a useful additive since it iswater-soluble and contains significant hydrophobic parts to bind drug:paclitaxel is 89% to 98% protein-bound after human intravenous infusion,and rapamycin is 92% protein bound, primarily (97%) to albumin.Furthermore, paclitaxel solubility in PBS increases over 20-fold withthe addition of BSA. Albumin is naturally present at high concentrationsin serum and is thus very safe for human use.

Other useful proteins include, without limitation, other albumins,immunoglobulins, caseins, hemoglobins, lysozymes, immunoglobins,a-2-macroglobulin, fibronectins, vitronectins, firbinogens, lipases, andthe like.

Organic Acids and their Esters and Anhydrides.

Examples are acetic acid and anhydride, benzoic acid and anhydride,diethylenetriaminepentaacetic acid dianhydride,ethylenediaminetetraacetic dianhydride, maleic acid and anhydride,succinic acid and anhydride, diglycolic anhydride, glutaric anhydride,ascorbic acid, citric acid, tartaric acid, lactic acid, oxalic acidaspartic acid, nicotinic acid, 2-pyrrolidone-5-carboxylic acid, and2-pyrrolidone.

These esters and anhydrides are soluble in organic solvents such asethanol, acetone, methylethylketone, ethylacetate. The water insolubledrugs can be dissolved in organic solvent with these esters andanhydrides, then coated easily on to the medical device, then hydrolyzedunder high pH conditions. The hydrolyzed anhydrides or esters are acidsor alcohols, which are water soluble and can effectively carry the drugsoff the device into the vessel walls.

Other Chemical Compounds with One or More Hydroxyl, Amine, Carbonyl,Carboxyl, or Ester Moieties.

The additives according to embodiments include amino alcohols, alcohols,amines, acids, amides and hydroxyl acids in both cyclic and linearaliphatic and aromatic groups. Examples are L-ascorbic acid and itssalt, D-glucoascorbic acid and its salt, tromethamine, triethanolamine,diethanolamine, meglumine, glucamine, amine alcohols, glucoheptonicacid, glucomic acid, hydroxyl ketone, hydroxyl lactone, gluconolactone,glucoheptonolactone, glucooctanoic lactone, gulonic acid lactone,mannoic lactone, ribonic acid lactone, lactobionic acid, glucosamine,glutamic acid, benzyl alcohol, benzoic acid, hydroxybenzoic acid, propyl4-hydroxybenzoate, lysine acetate salt, gentisic acid, lactobionic acid,lactitol, sorbitol, glucitol, sugar phosphates, glucopyranose phosphate,sugar sulphates, sinapic acid, vanillic acid, vanillin, methyl paraben,propyl paraben, xylitol, 2-ethoxyethanol, sugars, galactose, glucose,ribose, mannose, xylose, sucrose, lactose, maltose, arabinose, lyxose,fructose, cyclodextrin, (2-hydroxypropyl)-cyclodextrin, acetaminophen,ibuprofen, retinoic acid, lysine acetate, gentisic acid, catechin,catechin gallate, tiletamine, ketamine, propofol, lactic acids, aceticacid, salts of any organic acid and amine described above, polyglycidol,glycerol, multiglycerols, galactitol, di(ethylene glycol), tri(ethyleneglycol), tetra(ethylene glycol), penta(ethylene glycol), poly(ethyleneglycol) oligomers, di(propylene glycol), tri(propylene glycol),tetra(propylene glycol, and penta(propylene glycol), poly(propyleneglycol) oligomers, a block copolymer of polyethylene glycol andpolypropylene glycol, and derivatives and combinations thereof.

Combinations of additives are also useful for purposes of the presentinvention.

One embodiment includes the combination or mixture of two additives, forexample, a first additive including a surfactant and a second additiveincluding a chemical compound with one or more hydroxyl, amine,carbonyl, carboxyl, or ester moieties.

The combination or mixture of the surfactant and the small water-solublemolecule (the chemical compounds with one or more hydroxyl, amine,carbonyl, carboxyl, or ester moieties) has advantages. Formulationsincluding mixtures of the two additives with water-insoluble drug are incertain cases superior to mixtures including either additive alone. Thehydrophobic drugs bind extremely water-soluble small molecules morepoorly than they do surfactants. They are often phase separated from thesmall water-soluble molecules, which can lead to suboptimal coatinguniformity and integrity. The water-insoluble drug has Log P higher thanboth that of the surfactant and that of small water-soluble molecules.However, Log P of the surfactant is typically higher than Log P of thechemical compounds with one or more hydroxyl, amine, carbonyl, carboxyl,or ester moieties. The surfactant has a relatively high Log P (usuallyabove 0) and the water soluble molecules have low Log P (usually below0). Some surfactants, when used as additives in embodiments of thepresent invention, adhere so strongly to the water-insoluble drug andthe surface of the medical device that drug is not able to rapidlyrelease from the surface of the medical device at the target site. Onthe other hand, some of the water-soluble small molecules (with one ormore hydroxyl, amine, carbonyl, carboxyl, or ester moieties) adhere sopoorly to the medical device that they release drug before it reachesthe target site, for example, into serum during the transit of a coatedballoon catheter to the site targeted for intervention. Surprisingly, byadjusting the ratio of the concentrations of the small hydrophilicmolecule and the surfactant in the formulation, the inventor has foundthat the coating stability during transit and rapid drug release wheninflated and pressed against tissues of the lumen wall at the targetsite of therapeutic intervention in certain cases is superior to aformulation including either additive alone. Furthermore, themiscibility and compatibility of the water-insoluble drug and the highlywater-soluble molecules is improved by the presence of the surfactant.The surfactant also improves coating uniformity and integrity by itsgood adhesion to the drug and the small molecules. The long chainhydrophobic part of the surfactant binds drug tightly while thehydrophilic part of the surfactant binds the water-soluble smallmolecules.

The surfactants in the mixture or the combination include all of thesurfactants described herein for use in embodiments of the invention.The surfactant in the mixture may be chosen from PEG sorbitan fattyesters, PEG omega-3 fatty esters and alcohols, glycerol fatty esters,sorbitan fatty esters, PEG glyceryl fatty esters, PEG fatty esters,sugar fatty esters, PEG sugar esters, Tween 20, Tween 40, Tween 60,p-isononylphenoxypolyglycidol, PEG laurate, PEG oleate, PEG stearate,PEG glyceryl laurate, PEG glyceryl oleate, PEG glyceryl stearate,polyglyceryl laurate, plyglyceryl oleate, polyglyceryl myristate,polyglyceryl palmitate, polyglyceryl-6 laurate, plyglyceryl-6 oleate,polyglyceryl-6 myristate, polyglyceryl-6 palmitate, polyglyceryl-10laurate, plyglyceryl-10 oleate, polyglyceryl-10 myristate,polyglyceryl-10 palmitate, PEG sorbitan monolaurate, PEG sorbitanmonolaurate, PEG sorbitan monooleate, PEG sorbitan stearate, PEG oleylether, PEG laurayl ether, Tween 20, Tween 40, Tween 60, Tween 80,octoxynol, monoxynol, tyloxapol, sucrose monopalmitate, sucrosemonolaurate, decanoyl-N-methylglucamide, n-decyl-β-D-glucopyranoside,n-decyl-β-D-maltopyranoside, n-dodecyl-β-D-glucopyranoside,n-dodecyl-β-D-maltoside, heptanoyl-N-methylglucamide,n-heptyl-β-D-glucopyranoside, n-heptyl-β-D-thioglucoside,n-hexyl-β-D-glucopyranoside, nonanoyl-N-methylglucamide,n-nonyl-β-D-glucopyranoside, octanoyl-N-methylglucamide,n-octyl-β-D-glucopyranoside, octyl-β-D-thioglucopyranoside and theirderivatives.

The chemical compound with one or more hydroxyl, amine, carbonyl,carboxyl, or ester moieties in the mixture or the combination includeall of the chemical compounds with one or more hydroxyl, amine,carbonyl, carboxyl, or ester moieties described herein for use inembodiments of the invention. The chemical compound with one or morehydroxyl, amine, carbonyl, carboxyl, or ester moieties in the mixturehas at least one hydroxyl group in one of the embodiments in theinventions. In certain embodiments, additives with more than fourhydroxyl groups are utilized, for example in the case of a highmolecular weight additive. In some embodiments, the chemical compoundhaving more than four hydroxyl groups has a melting point of 120° C. orless. Large molecules diffuse slowly. If the molecular weight of theadditive or the chemical compound is high, for example if the molecularweight is above 800, above 1000, above 1200, above 1500, or above 2000;large molecules may elute off of the surface of the medical device tooslowly to release drug under 2 minutes. If these large molecules containmore than four hydroxyl groups they have increased hydrophilicproperties, which is necessary for relatively large molecules to releasedrug quickly. The increased hydrophilicity helps elute the coating offthe balloon, accelerates release of drug, and improves or facilitatesdrug movement through water barrier and polar head groups of lipidbilayers to penetrate tissues. In one embodiment, the hydroxyl group isutilized as the hydrophilic moiety because it is unlikely to react withwater insoluble drug, such as paclitaxel or rapamycin.

The chemical compound with one or more hydroxyl, amine, carbonyl,carboxyl, or ester moieties in the mixture is chosen from L-ascorbicacid and its salt, D-glucoascorbic acid and its salt, tromethamine,triethanolamine, diethanolamine, meglumine, glucamine, amine alcohols,glucoheptonic acid, glucomic acid, hydroxyl ketone, hydroxyl lactone,gluconolactone, glucoheptonolactone, glucooctanoic lactone, gulonic acidlactone, mannoic lactone, ribonic acid lactone, lactobionic acid,glucosamine, glutamic acid, benzyl alcohol, benzoic acid, hydroxybenzoicacid, propyl 4-hydroxybenzoate, lysine acetate salt, gentisic acid,lactobionic acid, lactitol, sorbitol, glucitol, sugar phosphates,glucopyranose phosphate, sugar sulphates, sinapic acid, vanillic acid,vanillin, methyl paraben, propyl paraben, xylitol, 2-ethoxyethanol,sugars, galactose, glucose, ribose, mannose, xylose, sucrose, lactose,maltose, arabinose, lyxose, fructose, cyclodextrin,(2-hydroxypropyl)-cyclodextrin, acetaminophen, ibuprofen, retinoic acid,lysine acetate, gentisic acid, catechin, catechin gallate, tiletamine,ketamine, propofol, lactic acids, acetic acid, salts of any organic acidand amine described above, polyglycidol, glycerol, multiglycerols,galactitol, di(ethylene glycol), tri(ethylene glycol), tetra(ethyleneglycol), penta(ethylene glycol), poly(ethylene glycol) oligomers,di(propylene glycol), tri(propylene glycol), tetra(propylene glycol, andpenta(propylene glycol), poly(propylene glycol) oligomers, a blockcopolymer of polyethylene glycol and polypropylene glycol, andderivatives and combinations thereof.

Mixtures or combinations of a surfactant and a water-soluble smallmolecule confer the advantages of both additives. The water insolubledrug often has a poor compatibility with highly water-soluble chemicalcompounds, and the surfactant improves compatibility. The surfactantalso improves the coating quality, uniformity, and integrity, andparticles do not fall off the balloon during handling. The surfactantreduces drug loss during transit to a target site. The water-solublechemical compound improves the release of drug off the balloon andabsorption of the drug in the tissue. Experimentally, the combinationwas surprisingly effective at preventing drug release during transit andachieving high drug levels in tissue after very brief 0.2-2 minutedeployment. Furthermore, in animal studies it effectively reducedstenosis and late lumen loss.

Some of the mixtures or combinations of surfactants and water-solublesmall molecules are very stable under heating. They survived an ethyleneoxide sterilization process and do not react with the water insolubledrug paclitaxel or rapamycin during sterilization. In one embodiment,the hydroxyl, ester, amide groups are utilized because they are unlikelyto react with therapeutic agents such as paclitaxel or rapamycin.Sometimes amine and acid groups do react with paclitaxel and are notstable under ethylene oxide sterilization, heating, and aging. When themixtures or combinations described herein are formulated withpaclitaxel, a top coat layer may be advantageous in order to protect thedrug layer and from premature drug loss during the device.

Examples of additives include p-isononylphenoxypolyglycidol, PEGglyceryl oleate, PEG glyceryl stearate, polyglyceryl laurate,plyglyceryl oleate, polyglyceryl myristate, polyglyceryl palmitate,polyglyceryl-6 laurate, plyglyceryl-6 oleate, polyglyceryl-6 myristate,polyglyceryl-6 palmitate, polyglyceryl-10 laurate, plyglyceryl-10oleate, polyglyceryl-10 myristate, polyglyceryl-10 palmitate, PEGsorbitan monolaurate, PEG sorbitan monolaurate, PEG sorbitan monooleate,PEG sorbitan stearate, octoxynol, monoxynol, tyloxapol, sucrosemonopalmitate, sucrose monolaurate, decanoyl-N-methylglucamide,n-decyl-β-D-glucopyranoside, n-decyl-β-D-maltopyranoside,n-dodecyl-β-D-glucopyranoside, n-dodecyl-β-D-maltoside,heptanoyl-N-methylglucamide, n-heptyl-Q-D-glucopyranoside,n-heptyl-β-D-thioglucoside, n-hexyl-β-D-glucopyranoside,nonanoyl-N-methylglucamide, n-nonyl-Q-D-glucopyranoside,octanoyl-N-methylglucamide, n-octyl-β-D-glucopyranoside,octyl-β-D-thioglucopyranoside; cystine, tyrosine, tryptophan, leucine,isoleucine, phenylalanine, asparagine, aspartic acid, glutamic acid, andmethionine (amino acids), cetotiamine, cyclothiamine, dexpanthenol,niacinamide, nicotinic acid and its salt, pyridoxal 5-phosphate,nicotinamide ascorbate, riboflavin, riboflavin phosphate, thiamine,folic acid, menadiol diphosphate, menadione sodium bisulfite,menadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin K6, and vitaminU (vitamins); albumin, immunoglobulins, caseins, hemoglobins, lysozymes,immunoglobins, a-2-macroglobulin, fibronectins, vitronectins,firbinogens, lipases, benzalkonium chloride, benzethonium chloride,docecyl trimethyl ammonium bromide, sodium docecylsulfates, dialkylmethylbenzyl ammonium chloride, and dialkylesters of sodiumsulfonsuccinic acid, L-ascorbic acid and its salt, D-glucoascorbic acidand its salt, tromethamine, triethanolamine, diethanolamine, meglumine,glucamine, amine alcohols, glucoheptonic acid, glucomic acid, hydroxylketone, hydroxyl lactone, gluconolactone, glucoheptonolactone,glucooctanoic lactone, gulonic acid lactone, mannoic lactone, ribonicacid lactone, lactobionic acid, glucosamine, glutamic acid, benzylalcohol, benzoic acid, hydroxybenzoic acid, propyl 4-hydroxybenzoate,lysine acetate salt, gentisic acid, lactobionic acid, lactitol, sinapicacid, vanillic acid, vanillin, methyl paraben, propyl paraben, sorbitol,xylitol, cyclodextrin, (2-hydroxypropyl)-cyclodextrin, acetaminophen,ibuprofen, retinoic acid, lysine acetate, gentisic acid, catechin,catechin gallate, tiletamine, ketamine, propofol, lactic acids, aceticacid, salts of any organic acid and organic amine, polyglycidol,glycerol, multiglycerols, galactitol, di(ethylene glycol), tri(ethyleneglycol), tetra(ethylene glycol), penta(ethylene glycol), poly(ethyleneglycol) oligomers, di(propylene glycol), tri(propylene glycol),tetra(propylene glycol, and penta(propylene glycol), poly(propyleneglycol) oligomers, a block copolymer of polyethylene glycol andpolypropylene glycol, and derivatives and combinations thereof. Examplesof additives include chemical compounds with one or more hydroxyl,amino, carbonyl, carboxyl, or ester moieties. Some of these additivesare both water-soluble and organic solvent-soluble. They have goodadhesive properties and adhere to the surface of polyamide medicaldevices, such as balloon catheters. They may therefore be used in theadherent layer, top layer, and/or in the drug layer of embodiments ofthe present invention. The aromatic and aliphatic groups increase thesolubility of water insoluble drugs in the coating solution, and thepolar groups of alcohols and acids accelerate drug permeation of tissue.

Other additives according to embodiments of the invention includehydroxyl ketone, hydroxyl lactone, hydroxyl acid, hydroxyl ester, andhydroxyl amide. Examples are gluconolactone, D-glucoheptono-1,4-lactone,glucooctanoic lactone, gulonic acid lactone, mannoic lactone, erythronicacid lactone, ribonic acid lactone, glucuronic acid, gluconic acid,gentisic acid, lactobionic acid, lactic acid, acetaminophen, vanillicacid, sinapic acid, hydroxybenzoic acid, methyl paraben, propyl paraben,and derivatives thereof.

From a structural point of view, these additives share structuralsimilarities and are compatible with water insoluble drugs (such aspaclitaxel and rapamycin). They often contain double bonds such as C═C,C═N, C═O in aromatic or aliphatic structures. These additives alsocontain amine, alcohol, ester, amide, anhydride, carboxylic acid, and/orhydroxyl groups. They may form hydrogen bonds and/or van der Waalsinteractions with drug. They are also useful in the top layer in thecoating. Compounds containing one or more hydroxyl, carboxyl, or aminegroups, for example, are especially useful as additives since theyfacilitate drug release from the device surface and easily displacewater next to the polar head groups and surface proteins of cellmembranes and may thereby remove this barrier to hydrophobic drugpermeability. They accelerate movement of a hydrophobic drug off theballoon to the lipid layer of cell membranes and tissues for which ithas very high affinity. They may also carry or accelerate the movementof drug off the balloon into more aqueous environments such as theinterstitial space, for example, of nonvascular tissues that have beeninjured by balloon angioplasty or stent expansion. Additives such aspolyglyceryl fatty esters, ascorbic ester of fatty acids, sugar esters,alcohols and ethers of fatty acids have fatty chains that can integrateinto the lipid structure of target tissue membranes, carrying drug tolipid structures. Some of the amino acids, vitamins and organic acidshave aromatic C═N groups as well as amino, hydroxyl, and carboxyliccomponents to their structure. They have structural parts that can bindor complex with hydrophobic drug, such as paclitaxel or rapamycin, andthey also have structural parts that facilitate tissue penetration byremoving barriers between hydrophobic drug and lipid structure of cellmembranes.

For example, isononylphenylpolyglycidol (Olin-10 G and Surfactant-10G),PEG glyceryl monooleate, sorbitan monolaurate (Arlacel 20), sorbitanmonopalmitate (Span-40), sorbitan monooleate (Span-80), sorbitanmonostearate, polyglyceryl-10 oleate, polyglyceryl-10 laurate,polyglyceryl-10 palmitate, and polyglyceryl-10 stearate all have morethan four hydroxyl groups in their hydrophilic part. These hydroxylgroups have very good affinity for the vessel wall and can displacehydrogen-bound water molecules. At the same time, they have long chainsof fatty acid, alcohol, ether and ester that can both complex withhydrophobic drug and integrate into the lipid structure of the cellmembranes to form the part of the lipid structure. This deformation orloosening of the lipid membrane of target cells may further acceleratepermeation of hydrophobic drug into tissue.

For another example, L-ascorbic acid, thiamine, maleic acids,niacinamide, and 2-pyrrolidone-5-carboxylic acid all have a very highwater and ethanol solubility and a low molecular weight and small size.They also have structural components including aromatic C═N, amino,hydroxyl, and carboxylic groups. These structures have very goodcompatibility with paclitaxel and rapamycin and can increase thesolubility of these water-insoluble drugs in water and enhance theirabsorption into tissues. However, they often have poor adhesion to thesurface of medical devices. They are therefore used in combination withother additives in the drug layer and top layer where they are useful toenhance drug absorption. Vitamin D2 and D3 are especially useful becausethey themselves have anti-restenotic effects and reduce thrombosis,especially when used in combination with paclitaxel.

In embodiments of the present invention, the additive is soluble inaqueous solvents and is soluble in organic solvents. Extremelyhydrophobic compounds that lack sufficient hydrophilic parts and areinsoluble in aqueous solvent, such as the dye Sudan Red, are not usefulas additives in these embodiments. Sudan red is also genotoxic.

In one embodiment, the concentration density of the at least onetherapeutic agent applied to the surface of the medical device is fromabout 1 to 20 μg/mm², or from about 2 to 6 μg/mm², or about 0.5microgram/mm² or less, or less than, equal to, or greater than about 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or about 20 micrograms/mm²or more. In one embodiment, the concentration of the at least oneadditive applied to the surface of the medical device is from about 0.5to 20 μg/mm², or from about 2 to 6 μg/mm², or about 0.5 microgram/mm² orless, or less than, equal to, or greater than about 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 12, 14, 16, 18, or about 20 micrograms/mm² or more. The ratioof additives to drug by weight in the coating layer in embodiments ofthe present invention is about 20 to 0.05, about 10 to 0.1, or about 5to 0.15.

The relative amount of the therapeutic agent and the additive in thecoating layer, may vary depending on applicable circumstances. Theoptimal amount of the additive can depend upon, for example, theparticular therapeutic agent and additive selected, the critical micelleconcentration of the surface modifier if it forms micelles, thehydrophilic-lipophilic-balance (HLB) of a surfactant or an additive'soctonol-water partition coefficient (P), the melting point of theadditive, the water solubility of the additive and/or therapeutic agent,the surface tension of water solutions of the surface modifier, etc.

Other considerations will further inform the choice of specificproportions of different additives. These considerations include thedegree of bioacceptability of the additives and the desired dosage ofhydrophobic therapeutic agent to be provided.

Therapeutic Agent.

The drugs or biologically active materials, which can be used inembodiments of the present invention, can be any therapeutic agent orsubstance. The drugs can be of various physical states, e.g., moleculardistribution, crystal forms or cluster forms. Examples of drugs that areespecially useful in embodiments of the present invention are lipophilicsubstantially water insoluble drugs, such as paclitaxel, rapamycin,daunorubicin, doxorubicin, lapachone, vitamin D2 and D3 and analoguesand derivatives thereof. These drugs are especially suitable for use ina coating on a balloon catheter used to treat tissue of the vasculature.

Other drugs that may be useful in embodiments of the present inventioninclude, without limitation, glucocorticoids (e.g., dexamethasone,betamethasone), hirudin, angiopeptin, aspirin, growth factors, antisenseagents, anti-cancer agents, anti-proliferative agents, oligonucleotides,and, more generally, anti-platelet agents, anti-coagulant agents,anti-mitotic agents, antioxidants, anti-metabolite agents,anti-chemotactic, and anti-inflammatory agents.

Some drugs that are considered particularly suitable for the airway,sinus and other nasal lumens are corticosteroids such as, budesonide,flunisolide, triamcinolone, beclomethasone, fluticasone, mometasone,mometasone furoate, dexamethasone, hydrocortisone, methylprednisolone,prednisone, cortisone, betamethasone, triamcinolone acetonide, or thelike. Some other suitable drugs are bronchodilators such as terbutaline,albuterol, ipratropium, pirbuterol, epinephrine, salmeterol,levalbuterol, formoterol, or the like.

Also useful in embodiments of the present invention are polynucleotides,antisense, RNAi, or siRNA, for example, that inhibit inflammation and/orsmooth muscle cell or fibroblast proliferation.

Anti-platelet agents can include drugs such as aspirin and dipyridamole.Aspirin is classified as an analgesic, antipyretic, anti-inflammatoryand anti-platelet drug. Dipyridamole is a drug similar to aspirin inthat it has anti-platelet characteristics. Dipyridamole is alsoclassified as a coronary vasodilator. Anti-coagulant agents for use inembodiments of the present invention can include drugs such as heparin,protamine, hirudin and tick anticoagulant protein. Anti-oxidant agentscan include probucol. Anti-proliferative agents can include drugs suchas amlodipine and doxazosin. Anti-mitotic agents and anti-metaboliteagents that can be used in embodiments of the present invention includedrugs such as methotrexate, azathioprine, vincristine, vinblastine,5-fluorouracil, adriamycin, and mutamycin. Antibiotic agents for use inembodiments of the present invention include penicillin, cefoxitin,oxacillin, tobramycin, and gentamicin. Suitable antioxidants for use inembodiments of the present invention include probucol. Additionally,genes or nucleic acids, or portions thereof can be used as thetherapeutic agent in embodiments of the present invention. Furthermore,collagen-synthesis inhibitors, such as tranilast, can be used as atherapeutic agent in embodiments of the present invention.

Photosensitizing agents for photodynamic or radiation therapy, includingvarious porphyrin compounds such as porfimer, for example, are alsouseful as drugs in embodiments of the present invention.

Drugs for use in embodiments of the present invention also includeeverolimus, somatostatin, tacrolimus, roxithromycin, dunaimycin,ascomycin, bafilomycin, erythromycin, midecamycin, josamycin,concanamycin, clarithromycin, troleandomycin, folimycin, cerivastatin,simvastatin, lovastatin, fluvastatin, rosuvastatin, atorvastatin,pravastatin, pitavastatin, vinblastine, vincristine, vindesine,vinorelbine, etoposide, teniposide, nimustine, carmustine, lomustine,cyclophosphamide, 4-hydroxycyclophosphamide, estramustine, melphalan,ifosfamide, trofosfamide, chlorambucil, bendamustine, dacarbazine,busulfan, procarbazine, treosulfan, temozolomide, thiotepa,daunorubicin, doxorubicin, aclarubicin, epirubicin, mitoxantrone,idarubicin, bleomycin, mitomycin, dactinomycin, methotrexate,fludarabine, fludarabine-5′-dihydrogenphosphate, cladribine,mercaptopurine, thioguanine, cytarabine, fluorouracil, gemcitabine,capecitabine, docetaxel, carboplatin, cisplatin, oxaliplatin, amsacrine,irinotecan, topotecan, hydroxycarbamide, miltefosine, pentostatin,aldesleukin, tretinoin, asparaginase, pegaspargase, anastrozole,exemestane, letrozole, formestane, aminoglutethimide, adriamycin,azithromycin, spiramycin, cepharantin, smc proliferation inhibitor-2w,epothilone A and B, mitoxantrone, azathioprine, mycophenolatmofetil,c-myc-antisense, b-myc-antisense, betulinic acid, camptothecin,lapachol, beta.-lapachone, podophyllotoxin, betulin, podophyllic acid2-ethylhydrazide, molgramostim (rhuGM-CSF), peginterferon a-2b,lenograstim (r-HuG-CSF), filgrastim, macrogol, dacarbazine, basiliximab,daclizumab, selectin (cytokine antagonist), CETP inhibitor, cadherines,cytokinin inhibitors, COX-2 inhibitor, NFkB, angiopeptin, ciprofloxacin,camptothecin, fluoroblastin, monoclonal antibodies, which inhibit themuscle cell proliferation, bFGF antagonists, probucol, prostaglandins,1,11-dimethoxycanthin-6-one, 1-hydroxy-11-methoxycanthin-6-one,scopoletin, colchicine, NO donors such as pentaerythritol tetranitrateand syndnoeimines, S-nitrosoderivatives, tamoxifen, staurosporine,beta.-estradiol, a-estradiol, estriol, estrone, ethinylestradiol,fosfestrol, medroxyprogesterone, estradiol cypionates, estradiolbenzoates, tranilast, kamebakaurin and other terpenoids, which areapplied in the therapy of cancer, verapamil, tyrosine kinase inhibitors(tyrphostines), cyclosporine A, 6-a-hydroxy-paclitaxel, baccatin,taxotere and other macrocyclic oligomers of carbon suboxide (MCS) andderivatives thereof, mofebutazone, acemetacin, diclofenac, lonazolac,dapsone, o-carbamoylphenoxyacetic acid, lidocaine, ketoprofen, mefenamicacid, piroxicam, meloxicam, chloroquine phosphate, penicillamine,hydroxychloroquine, auranofin, sodium aurothiomalate, oxaceprol,celecoxib, P-sitosterin, ademetionine, myrtecaine, polidocanol, nonivamide, levomenthol, benzocaine, aescin, ellipticine, D-24851(Calbiochem), colcemid, cytochalasin A-E, indanocine, nocodazole, S 100protein, bacitracin, vitronectin receptor antagonists, azelastine,guanidyl cyclase stimulator tissue inhibitor of metal proteinase-1 and-2, free nucleic acids, nucleic acids incorporated into virustransmitters, DNA and RNA fragments, plasminogen activator inhibitor-1,plasminogen activator inhibitor-2, antisense oligonucleotides, VEGFinhibitors, IGF-1, active agents from the group of antibiotics such ascefadroxil, cefazolin, cefaclor, cefotaxim, tobramycin, gentamycin,penicillins such as dicloxacillin, oxacillin, sulfonamides,metronidazol, antithrombotics such as argatroban, aspirin, abciximab,synthetic antithrombin, bivalirudin, coumadin, enoxaparin, desulphatedand N-reacetylated heparin, tissue plasminogen activator, GpIIb/IIIaplatelet membrane receptor, factor Xa inhibitor antibody, heparin,hirudin, r-hirudin, PPACK, protamin, prourokinase, streptokinase,warfarin, urokinase, vasodilators such as dipyramidole, trapidil,nitroprussides, PDGF antagonists such as triazolopyrimidine and seramin,ACE inhibitors such as captopril, cilazapril, lisinopril, enalapril,losartan, thiol protease inhibitors, prostacyclin, vapiprost, interferona, .beta and y, histamine antagonists, serotonin blockers, apoptosisinhibitors, apoptosis regulators such as p65 NF-kB or BcI-xL antisenseoligonucleotides, halofuginone, nifedipine, tranilast, molsidomine, teapolyphenols, epicatechin gallate, epigallocatechin gallate, Boswellicacids and derivatives thereof, leflunomide, anakinra, etanercept,sulfasalazine, etoposide, dicloxacillin, tetracycline, triamcinolone,mutamycin, procainamide, retinoic acid, quinidine, disopyramide,flecamide, propafenone, sotalol, amidorone, natural and syntheticallyobtained steroids such as bryophyllin A, inotodiol, maquiroside A,ghalakinoside, mansonine, strebloside, hydrocortisone, betamethasone,dexamethasone, non-steroidal substances (NSAIDS) such as fenoprofen,ibuprofen, indomethacin, naproxen, phenylbutazone and other antiviralagents such as acyclovir, ganciclovir and zidovudine, antimycotics suchas clotrimazole, flucytosine, griseofulvin, ketoconazole, miconazole,nystatin, terbinafine, antiprozoal agents such as chloroquine,mefloquine, quinine, moreover natural terpenoids such as hippocaesculin,barringtogenol-C21-angelate, 14-dehydroagrostistachin, agroskerin,agrostistachin, 17-hydroxyagrostistachin, ovatodiolids,4,7-oxycycloanisomelic acid, baccharinoids B1, B2, B3 and B7,tubeimoside, bruceanol A, B and C, bruceantinoside C, yadanziosides Nand P, isodeoxyelephantopin, tomenphantopin A and B, coronarin A, B, Cand D, ursolic acid, hyptatic acid A, zeorin, iso-iridogermanal,maytenfoliol, effusantin A, excisanin A and B, longikaurin B,sculponeatin C, kamebaunin, leukamenin A and B,13,18-dehydro-6-a-senecioyloxychaparrin, taxamairin A and B, regenilol,triptolide, moreover cymarin, apocymarin, aristolochic acid, anopterin,hydroxyanopterin, anemonin, protoanemonin, berberine, cheliburinchloride, cictoxin, sinococuline, bombrestatin A and B, cudraisoflavoneiA, curcumin, dihydronitidine, nitidine chloride,12-beta-hydroxypregnadien-3,20-dione, bilobol, ginkgol, ginkgolic acid,helenalin, indicine, indicine-N-oxide, lasiocarpine, inotodiol,glycoside la, podophyllotoxin, justicidin A and B, larreatin,malloterin, mallotochromanol, isobutyrylmallotochromanol, maquiroside A,marchantin A, maytansine, lycoridicin, margetine, pancratistatin,liriodenine, bisparthenolidine, oxoushinsunine, aristolactam-AII,bisparthenolidine, periplocoside A, ghalakinoside, ursolic acid,deoxypsorospermin, psychorubin, ricin A, sanguinarine, manwu wheat acid,methylsorbifolin, sphatheliachromen, stizophyllin, mansonine,strebloside, akagerine, dihydrousambarensine, hydroxyusambarine,strychnopentamine, strychnophylline, usambarine, usambarensine,berberine, liriodenine, oxoushinsunine, daphnoretin, lariciresinol,methoxylariciresinol, syringaresinol, umbelliferon, afromoson,acetylvismione B, desacetylvismione A, and vismione A and B.

A combination of drugs can also be used in embodiments of the presentinvention. Some of the combinations have additive effects because theyhave a different mechanism, such as paclitaxel and rapamycin, paclitaxeland active vitamin D, paclitaxel and lapachone, rapamycin and activevitamin D, rapamycin and lapachone. Because of the additive effects, thedose of the drug can be reduced as well. These combinations may reducecomplications from using a high dose of the drug.

Adherent Layer.

The adherent layer, which is an optional layer underlying the drugcoating layer, improves the adherence of the drug coating layer to theexterior surface of the medical device and protects coating integrity.If drug and additive differ in their adherence to the medical device,the adherent layer may prevent differential loss (during transit) orelution (at the target site) of drug layer components in order tomaintain consistent drug-to-additive or drug-to-drug ratio in the druglayer and therapeutic delivery at the target site of intervention.Furthermore, the adherent layer may function to facilitate release ofcoating layer components which otherwise might adhere too strongly tothe device for elution during brief contact with tissues at the targetsite. For example, in the case where a particular drug binds the medicaldevice tightly, more hydrophilic components are incorporated into theadherent layer in order to decrease affinity of the drug to the devicesurface.

As described above, the adherent layer includes a polymer or an additiveor mixtures of both. The polymers that are useful for forming theadherent layer are ones that are biocompatible and avoid irritation ofbody tissue. Some examples of polymers that are useful for forming theadherent layer are polymers that are biostable, such as polyurethanes,silicones, and polyesters. Other polymers that are useful for formingthe adherent layer include polymers that can be dissolved andpolymerized on the medical device.

Some examples of polymers that are useful in the adherent layer ofembodiments of the present invention include polyolefins,polyisobutylene, ethylene-1-olefin copolymers, acrylic polymers andcopolymers, polyvinyl chloride, polyvinyl methyl ether, polyvinylidenefluoride and polyvinylidene chloride, polyacrylonitrile, polyvinylketones, polystyrene, polyvinyl acetate, ethylene-methyl methacrylatecopolymers, acrylonitrile-styrene copolymers, ABS resins, Nylon 12 andits block copolymers, polycaprolactone, polyoxymethylenes, polyethers,epoxy resins, polyurethanes, rayon-tri acetate, cellulose, celluloseacetate, cellulose butyrate, cellophane, cellulose nitrate, cellulosepropionate, cellulose ethers, carboxymethyl cellulose, chitins,polylactic acid, polyglycolic acid, polylactic acid-polyethylene oxidecopolymers, polyethylene glycol, polypropylene glycol, polyvinylalcohol, and mixtures and block copolymers thereof.

Since the medical device undergoes mechanical manipulation, i.e.,expansion and contraction, examples of polymers that are useful in theadherent layer include elastomeric polymers, such as silicones (e.g.,polysiloxanes and substituted polysiloxanes), polyurethanes,thermoplastic elastomers, ethylene vinyl acetate copolymers, polyolefinelastomers, and EPDM rubbers. Due to the elastic nature of thesepolymers, when these polymers are used, the coating better adheres tothe surface of the medical device when the device is subjected to forcesor stress.

The adherent layer may also include one or more of the additivespreviously described, or other components, in order to maintain theintegrity and adherence of the coating layer to the device and tofacilitate both adherence of drug and additive components during transitand rapid elution during deployment at the site of therapeuticintervention.

Top Layer.

In order to further protect the integrity of the drug layer, an optionaltop layer may be applied to prevent loss of drug during transit throughtortuous anatomy to the target site or during the initial expansion ofthe device before the coating makes direct contact with target tissue.The top layer may release slowly in the body lumen while protecting thedrug layer. The top layer will erode more slowly if it is included ofmore hydrophobic, high molecular weight additives. Surfactants areexamples of more hydrophobic structures with long fatty chains, such asTween 20 and polyglyceryl oleate. High molecular weight additivesinclude polyethylene oxide, polyethylene glycol, and polyvinylpyrrolidone. Hydrophobic drug itself can act as a top layer component.For example, paclitaxel or rapamycin are hydrophobic. They can be usedin the top layer. On the other hand, the top layer cannot erode tooslowly or it might actually slow the release of drug during deploymentat the target site. Other additives useful in the top coat includeadditives that strongly interact with drug or with the coating layer,such as p-isononylphenoxypolyglycidol, PEG laurate, Tween 20, Tween 40,Tween 60, Tween 80, PEG oleate, PEG stearate, PEG glyceryl laurate, PEGglyceryl oleate, PEG glyceryl stearate, polyglyceryl laurate,plyglyceryl oleate, polyglyceryl myristate, polyglyceryl palmitate,polyglyceryl-6 laurate, plyglyceryl-6 oleate, polyglyceryl-6 myristate,polyglyceryl-6 palmitate, polyglyceryl-10 laurate, plyglyceryl-10oleate, polyglyceryl-10 myristate, polyglyceryl-10 palmitate PEGsorbitan monolaurate, PEG sorbitan monolaurate, PEG sorbitan monooleate,PEG sorbitan stearate, PEG oleyl ether, PEG laurayl ether, octoxynol,monoxynol, tyloxapol, sucrose monopalmitate, sucrose monolaurate,decanoyl-N-methylglucamide, n-decyl-β-D-glucopyranoside,n-decyl-β-D-maltopyranoside, n-dodecyl-β-D-glucopyranoside,n-dodecyl-β-D-maltoside, heptanoyl-N-methylglucamide,n-heptyl-β-D-glucopyranoside, n-heptyl-β-D-thioglucoside,n-hexyl-β-D-glucopyranoside, nonanoyl-N-methylglucamide,n-nonyl-β-D-glucopyranoside, octanoyl-N-methylglucamide,n-octyl-β-D-glucopyranoside, octyl-β-D-thioglucopyranoside; cystine,tyrosine, tryptophan, leucine, isoleucine, phenylalanine, asparagine,aspartic acid, glutamic acid, and methionine; acetic anhydride, benzoicanhydride, ascorbic acid, 2-pyrrolidone-5-carboxylic acid, sodiumpyrrolidone carboxylate, ethylenediaminetetraacetic dianhydride, maleicand anhydride, succinic anhydride, diglycolic anhydride, glutaricanhydride, acetiamine, benfotiamine, pantothenic acid, cetotiamine,cyclothiamine, dexpanthenol, niacinamide, nicotinic acid, pyridoxal5-phosphate, nicotinamide ascorbate, riboflavin, riboflavin phosphate,thiamine, folic acid, menadiol diphosphate, menadione sodium bisulfite,menadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin K6, and vitaminU; albumin, immunoglobulins, caseins, hemoglobins, lysozymes,immunoglobins, a-2-macroglobulin, fibronectins, vitronectins,firbinogens, lipases, benzalkonium chloride, benzethonium chloride,docecyl trimethyl ammonium bromide, sodium docecylsulfates, dialkylmethylbenzyl ammonium chloride, and dialkylesters of sodiumsulfonsuccinic acid, L-ascorbic acid and its salt, D-glucoascorbic acidand its salt, tromethamine, triethanolamine, diethanolamine, meglumine,glucamine, amine alcohols, glucoheptonic acid, glucomic acid, hydroxylketone, hydroxyl lactone, gluconolactone, glucoheptonolactone,glucooctanoic lactone, gulonic acid lactone, mannoic lactone, ribonicacid lactone, lactobionic acid, glucosamine, glutamic acid, benzylalcohol, benzoic acid, hydroxybenzoic acid, propyl 4-hydroxybenzoate,lysine acetate salt, gentisic acid, lactobionic acid, lactitol, sinapicacid, vanillic acid, vanillin, methyl paraben, propyl paraben, sorbitol,xylitol, cyclodextrin, (2-hydroxypropyl)-cyclodextrin, pentaerythritolethoxylate, pentaerythritol propoxylate, pentaerythritolpropoxylate/ethoxylate, glycerol ethoxylate, glycerol propoxylate,trimethylolpropane ethoxylate, pentaerythritol, dipentaerythritol, crownether, 18-crown-6, 15-crown-5, 12-crown-4, acetaminophen, ibuprofen,retinoic acid, lysine acetate, gentisic acid, catechin, catechingallate, tiletamine, ketamine, propofol, lactic acids, acetic acid,salts of any organic acid and organic amine, polyglycidol, glycerol,multiglycerols, galactitol, di(ethylene glycol), tri(ethylene glycol),tetra(ethylene glycol), penta(ethylene glycol), poly(ethylene glycol)oligomers, di(propylene glycol), tri(propylene glycol), tetra(propyleneglycol, and penta(propylene glycol), poly(propylene glycol) oligomers, ablock copolymer of polyethylene glycol and polypropylene glycol, andderivatives and combinations thereof.

Solvents.

Solvents for preparing of the coating layer may include, as examples,any combination of one or more of the following: (a) water, (b) alkanessuch as hexane, octane, cyclohexane, and heptane, (c) aromatic solventssuch as benzene, toluene, and xylene, (d) alcohols such as ethanol,propanol, and isopropanol, diethylamide, ethylene glycol monoethylether, Trascutol, and benzyl alcohol (e) ethers such as dioxane,dimethyl ether and tetrahydrofuran, (f) esters/acetates such as ethylacetate and isobutyl acetate, (g) ketones such as acetone, acetonitrile,diethyl ketone, and methyl ethyl ketone, and (h) mixture of water andorganic solvents such as water/ethanol, water/acetone, water/methanol,water/tetrahydrofuran. A solvent in the top coating layer is, forexample, methanol, ethanol, and acetone.

Organic solvents, such as short-chained alcohol, dioxane,tetrahydrofuran, dimethylformamide, acetonitrile, dimethylsulfoxide,etc., are particularly useful solvents in embodiments of the presentinvention because these organic solvents generally disrupt colloidalaggregates and co-solubilize all the components in the coating solution.

The therapeutic agent and additive or additives may be dispersed in,solubilized, or otherwise mixed in the solvent. The weight percent ofdrug and additives in the solvent may be in the range of 0.1-80% byweight, or 2-20% by weight.

Another embodiment of the invention relates to a method for preparing amedical device, particularly, for example, a balloon catheter or astent. First, a coating solution or suspension including at least onesolvent, at least one therapeutic agent, and at least one additive isprepared. In at least one embodiment, the coating solution or suspensionincludes only these three components. The content of the therapeuticagent in the coating solution can be from 0.5-50% by weight based on thetotal weight of the solution. The content of the additive in the coatingsolution can be from about 0.1 wt/o to about 45 wt %, about 0.2 wt % toabout 40 wt % by weight, about 0.3 to about 15 wt %, or about 0.1 wt %or less, or less than, equal to, or greater than about 0.2 wt %, 0.3,0.4, 0.5, 0.6, 0.8, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20,22, 24, 26, 28, 30, 35, 40, or about 45 wt % or more, based on the totalweight of the solution. The amount of solvent used depends on thecoating process and viscosity. It will affect the uniformity of thedrug-additive coating but will be evaporated.

In other embodiments, two or more solvents, two or more therapeuticagents, and/or two or more additives may be used in the coatingsolution.

In other embodiments, a therapeutic agent, an additive and a polymericmaterial may be used in the coating solution, for example in a stentcoating. In the coating, the therapeutic agent is not encapsulated inpolymer particles.

Various techniques may be used for applying a coating solution to amedical device such as casting, fixed volume liquid dispensing, metering(e.g., dispense a fixed amount of coating solution based on volume ontothe balloon), spinning, spraying, dipping (immersing), ink jet printing,electrostatic techniques, and combinations of these processes. Duringthe application of the coating solution, the balloon can be at leastpartially inflated. The metering can be performed in any suitable way,such as by pumping liquid coating solution from a reservoir to a nozzlethat is proximate the surface of the balloon (e.g., the surface of an atleast partially inflated balloon). The nozzle can dispense the liquidtherefrom, which can be immediately transferred to the exterior of theballoon due to its proximity to the nozzle (e.g., the nozzle can be soclose to the balloon that the liquid emerging from the nozzle cancontact and be transferred to the exterior of the balloon before forminga drop of liquid that leaves the nozzle). The nozzle can dispense theliquid to the exterior of the balloon such that substantially none ofthe liquid is lost. The balloon can be rotated around its longitudinalaxis during the dispensing of the liquid from the nozzle. The nozzle canmove during the dispensing, such as along the exterior of the balloonparallel to the longitudinal axis of the balloon. In some embodiments,the balloon can be rotated around its longitudinal axis during thedispensing, and the nozzle can move parallel to the longitudinal axis ofthe balloon, such that substantially all of the balloon surface iscoated with the coating solution (e.g., similar to the movement of awoodworker's chisel on a cylindrical piece of spinning wood in a lathe).

Choosing an application technique principally depends on the viscosityand surface tension of the solution. In some embodiments of the presentinvention, metering can be utilized because it makes it easier tocontrol the uniformity of the thickness of the coating layer as well asthe concentration of the therapeutic agent applied to the medicaldevice.

In one embodiment of the present invention, the balloon is inflated orpartially inflated, the coating solution is applied to the inflatedballoon by metering it on while the balloon is inflated and rotatingalong its longitudinal axis. The balloon is then allowed to dry beforebeing deflated, folded, and sheathed.

It should be understood that this description of an embodiment of anapplication device, fixture, and metering technique is an example. Anysuitable metering or other technique may be used for coating the medicaldevice, particularly for coating the balloon of a balloon catheter orstent delivery system or stent.

After the medical device is coated with the coating solution, the coatedballoon is subjected to a drying in which the solvent in the coatingsolution is evaporated. This produces a coating matrix on the ballooncontaining the therapeutic agent. One example of a drying technique isplacing a coated balloon into an oven at approximately 20° C. or higherfor approximately 24 hours. Any other suitable method of drying thecoating solution may be used. The time, temperature, and relativehumidity may vary with particular additives and therapeutic agents.

Optional Post Treatment.

After depositing the drug-additive containing layer on the device ofcertain embodiments of the present invention, dimethyl sulfoxide (DMSO)or other solvent may be applied, by dip or spray or other method, to thefinished surface of the coating. DMSO readily dissolves drugs and easilypenetrates membranes and may enhance tissue absorption.

It is contemplated that the medical devices of embodiments of thepresent invention have applicability for treating blockages andocclusions of any suitable body lumen, including, among others, thegastrointestinal tract, including the esophagus, stomach, smallintestine, and colon, the pulmonary airways, including the trachea,bronchi, bronchioles, the sinus, the biliary tract, the urinary tract,urethra, ureters, and prostatic urethra and other lumens. They areespecially suited for treating tissue of the urological tract with, forexample, a balloon catheter or a stent.

Yet another embodiment of the present invention relates to a method oftreating a prostate. The method includes inserting a medical deviceincluding a coating into a prostate. The coating layer includes atherapeutic agent and an additive. In this embodiment, the medicaldevice can be configured as having at least an expandable portion. Someexamples of such devices include balloon catheters, perfusion ballooncatheters, an infusion catheter such as distal perforated drug infusioncatheters, a perforated balloon, spaced double balloon, porous balloon,and weeping balloon, cutting balloon catheters, scoring ballooncatheters, self-expanded and balloon expanded-stents, guide catheters,guide wires, embolic protection devices, and various imaging devices.

As mentioned above, one example of a medical device that is particularlyuseful in the present invention is a coated balloon catheter. A ballooncatheter typically has a long, narrow, hollow tube tabbed with aminiature, deflated balloon. In embodiments of the present invention,the balloon is coated with a drug solution. Then, the balloon ismaneuvered through the stricture in the nonvascular body lumen to thesite of a blockage, occlusion, or other tissue requiring a therapeuticagent. Once in the proper position, the balloon is inflated and contactsthe walls of the stricture in the nonvascular body lumen and/or ablockage or occlusion. It is an object of embodiments of the presentinvention to rapidly deliver drug to and facilitate absorption by targettissue. It is advantageous to efficiently deliver drug to tissue in asbrief a period of time as possible while the device is deployed at thetarget site. The therapeutic agent is released into such tissue, forexample the lumen walls, in about 0.1 to 30 minutes, for example, orabout 0.1 to 10 minutes, or about 0.2 to 2 minutes, or about 0.1 to 1minutes, of balloon inflation time pressing the drug coating intocontact with diseased nonvascular tissue.

Given that a therapeutically effective amount of the drug can bedelivered by embodiments of the present invention into, for example, theprostate, in some cases the need for a stent may be eliminated,obviating the complications of fracture and dripping associatedtherewith.

Further, the balloon catheter may be used to treat nonvasculartissue/disease alone or in combination with other methods for treatingthe non vasculature, for example, direct vision internal urethrotomy(DVIU) for strictures andtransurethral resection of the prostate (TURP)for BPH. DVIU is a procedure used to open a urethral stricture.Specifically, DVIU is a procedure in which relaxing incisions are madein a stricture to create urethral luminal gain. DVIU may be accomplishedusing cold knife (urethrotome) or a hot knife (electrode). The cutter isinserted into the body and advanced through the urethra to the area ofnarrowing. After the relaxing insisions have been made, balloon dilationusing the coated balloon of embodiments of the present invention may beperformed. In addition, stenting may be performed thereafter, orsimultaneous with expansion of the coated balloon as described above.For TURP the medical device typically used is a hot knife (electrode) ora laser. In either case the device is inserted into the body andadvanced through the urethra to the area of narrowing. After theprostatic tissue has been excised, balloon dilation using the coatedballoon of embodiments of the present invention may be performed. Inaddition, stenting may be performed thereafter, or simultaneous withexpansion of the coated balloon as described above.

In some of the embodiments of drug-containing coatings and layersaccording to the present invention, the coating or layer does notinclude polymers, oils, or lipids. And, furthermore, in variousembodiments, the therapeutic agent is not encapsulated in polymerparticles, micelles, or liposomes. As described above, such formulationscan have significant disadvantages and can inhibit the intendedefficient, rapid release and tissue penetration of the agent, especiallyin the environment of diseased tissue of the nonvasculature.

Although various embodiments are specifically illustrated and describedherein, it will be appreciated that modifications and variations of thepresent invention are covered by the above teachings and are within thepurview of the appended claims without departing from the spirit andintended scope of the invention.

Other than the operating examples, or where otherwise indicated, allnumbers expressing quantities of components in a layer, reactionconditions, and so forth used in the specification and claims are to beunderstood as being modified in all instances by the term “about.”Accordingly, unless otherwise indicated to the contrary, the numericalparameters set forth in this specification and attached claims areapproximations that may vary depending upon the desired propertiessought to be obtained by the present disclosure.

Preparation.

The medical device and the coating layers of embodiments of the presentinvention can be made according to various methods. For example, thecoating solution can be prepared by dispersing, dissolving, diffusing,or otherwise mixing all the ingredients, such as a therapeutic agent, anadditive, and a solvent, simultaneously together. Also, the coatingsolution can be prepared by sequentially adding each component based onsolubility or any other parameters. For example, the coating solutioncan be prepared by first adding the therapeutic agent to the solvent andthen adding the additive. Alternatively, the additive can be added tothe solvent first and then the therapeutic agent can be later added. Ifthe solvent used does not sufficiently dissolve the drug, it is usefulto first add the additive to the solvent, then the drug, since theadditive will increase drug solubility in the solvent.

EXAMPLES

The following examples include embodiments of medical devices andcoating layers within the scope of the present invention. The examplesshould not be interpreted as limitations upon the present invention.

Example 1. Preparation of Coating Solutions

Formulation 1: 50-150 mg (0.06-0.18 mmole) paclitaxel, 25-300 mg PEG8caprylic/capric glycerides, and 2-6 ml ethanol were mixed.

Formulation 2: 50-150 mg (0.06-0.18 mmole) paclitaxel, 25-300 mg PEG8caprylic/capric glycerides, 25-300 mg uracil and 2-6 ml ethanol weremixed.

Formulation 3: 50-150 mg (0.06-0.18 mmole) paclitaxel, 25-300 mg PEG8caprylic/capric glycerides, 25-300 mg uridine and 2-6 ml ethanol weremixed.

Formulation 4: 50-150 mg (0.06-0.18 mmole) paclitaxel, 25-300 mg PEG8caprylic/capric glycerides, 25-300 mg sucralose and 2-6 ml ethanol weremixed.

Formulation 4a: 50-150 mg (0.06-0.18 mmole) paclitaxel, 25-300 mg PEG8caprylic/capric glycerides, 25-300 mg sucralose and 2-6 ml ethanol weremixed, with a mass ratio of paclitaxel:PEG8 caprylic/capricglycerides:sucralose of 1:1:1.

Formulation 4b: 50-150 mg (0.06-0.18 mmole) paclitaxel, 25-300 mg PEG8caprylic/capric glycerides, 25-300 mg sucralose and 2-6 ml ethanol weremixed, with a mass ratio of paclitaxel:PEG8 caprylic/capricglycerides:sucralose of 1:1:2.

Formulation 5: 50-150 mg (0.06-0.18 mmole) paclitaxel, 25-300 mg PEG8caprylic/capric glycerides, 25-300 mg creatinine and 2-6 ml ethanol weremixed.

Formulation 6: 50-150 mg (0.06-0.18 mmole) paclitaxel, 25-300 mg PEG6caprylic/capric glycerides, 25-300 mg uracil and 2-6 ml ethanol weremixed.

Formulation 7: 50-150 mg (0.06-0.18 mmole) paclitaxel, 25-300 mgC6-ceramide and 2-6 ml ethanol were mixed.

Formulation 8: 50-150 mg (0.06-0.18 mmole) paclitaxel, 25-300 mgmonolaurin, 25-300 mg sucralose and 2-6 ml ethanol were mixed.

Formulation 9: 50-150 mg (0.06-0.18 mmole) paclitaxel, 25-300 mgsucralose and 2-6 ml ethanol were mixed.

Formulation 10: 50-150 mg (0.06-0.18 mmole) paclitaxel, 25-300 mg PEG8mono caprylate/caprate and 1-6 ml ethanol were mixed.

Formulation 11: 50-150 mg (0.06-0.18 mmole) paclitaxel, 25-300 mg PEG8mono caprylate/caprate, 25-300 mg sucralose and 1-6 ml ethanol weremixed.

Formulation 12: 50-150 mg (0.06-0.18 mmole) paclitaxel, 25-300 mgthymidine, and 1-6 ml (96/4 v/v) THF/water were mixed.

Formulation 13: 50-150 mg (0.06-0.18 mmole) paclitaxel, 25-300 mguridine, and 1-6 ml (96/4 v/v) THF/water were mixed.

Formulation 14: 50-150 mg (0.06-0.18 mmole) paclitaxel, 25-300 mgcaffeine, and 1-6 ml (96/4 v/v) THF/water were mixed.

Formulation 15: 50-150 mg (0.06-0.18 mmole) paclitaxel, 25-300 mg18Crown6, and 1-6 ml ethanol were mixed.

Formulation 16: 50-150 mg (0.06-0.18 mmole) paclitaxel, 25-300 mg18Crown6, and 1-6 ml ethanol were mixed.

Formulation 17: 50-150 mg (0.06-0.18 mmole) paclitaxel, 10-100 mg18Crown6, 10-100 mg pentaerythritol ethoxylate (15/4) and 1-6 ml ethanolwere mixed.

Formulation 18: 50-150 mg (0.06-0.18 mmole) paclitaxel, 25-300 mgpentaerythritol ethoxylate (15/4), and 1-6 ml ethanol were mixed.

Formulation 19: 50-150 mg (0.06-0.18 mmole) paclitaxel, 25-300 mgtrimethylpropane ethoxylate (Mw-1014)), and 1-6 ml ethanol were mixed.

Formulation 20: 50-150 mg (0.06-0.18 mmole) paclitaxel, 25-300 mgpentaerythritol ethoxylate (3/4), and 1-6 ml ethanol were mixed.

Formulation 21: 50-150 mg (0.06-0.18 mmole) paclitaxel, 25-300 mg15Crown5, and 1-6 ml ethanol were mixed.

Formulation 22: 25-100 mg (0.03-0.12 mmole) paclitaxel, 25-300 mgthymidine, and 1-6 ml (90/10 v/v) THF/water were mixed.

Formulation 23: 50-150 mg (0.06-0.18 mmole) paclitaxel, 5-75 mgpentaerythritol ethoxylate (15/4), 10-200 mg pentaerythritol ethoxylate(3/4), and 1-6 ml ethanol were mixed.

Formulation 24: 50-150 mg (0.06-0.18 mmole) paclitaxel, 25-300 mgtrimethylpropane ethoxylate (Mw-170)), and 1-6 ml ethanol were mixed.

Example 2. Preclinical Study 1 & 2 Sample Preparation

Twenty one balloon catheters (twelve 4 mm in diameter and 40 mm inlength, six 8 mm in diameter and 40 mm in length, three 20 mm indiameter and 50 mm in length) were inflated to 1 to 2 atmospherespressure and wiped with an ethanol wipe to clean the balloon surface.Next the balloons were coated using various formulations (1-6) fromExample 1 with sufficient coating solution to achieve 2-4 microgrampaclitaxel per square mm of balloon surface. The balloons were thendried, folded, sheathed, packaged in a Tyvek pouch and ethylene oxidesterilized in preparation for animal testing.

Example 3. Preclinical Study 1 & 2 Treatments

For this study male dogs were used. Baseline urethrograms were taken tomeasure the inner diameter of the urethra treatment sites before drugcoated balloon treatment. Drug coated balloon catheters prepared inExample 2 were used with nonoverlapping treatments in the pelvic,bulbar, and distal urethra just proximal of the os penis. The os penisurethra was not treated. The treatment site diameters were approximately3.5-4.5 mm. The balloon catheters were chosen such that the nominaloverstretch ratio (the ratio of balloon diameter at nominal inflationpressure to urethra diameter) for the prostatic urethra balloons wasapproximately 4-6. For the anterior urethra, balloon catheters werechosen such that the nominal overstretch ratio was approximately1.8-2.3. Prior to inserting the catheter approximately 5 mL of salinewas used to flush the urethra. The 18-20 mm diameter balloons wereinflated in the prostatic urethra and the 8 mm balloons were inflated inthe anterior urethra. The 18 to 20 mm diameter balloons were inflated to4 atmospheres at the treatment sites for 10 min to release drug andadditive, then deflated and withdraw from the dogs. The 8 mm diameterballoons were inflated to 12 atmospheres at the treatment sites for 10min to release drug and additive, then deflated and withdraw from thedogs. The inflation overstretch ratio (the ratio of inflated balloondiameter to urethra diameter) for the inflated 20 mm diameter balloonswas 4.4 to 6.3. The overstretch ratio for the inflated 8 mm diameterballoons was 2.0 to 2.5. The amount of drug in the treated urethratissues of the sacrificed animal was measured after 4 hrs and 1 day andthe residual drug remaining on the balloon after use was analyzed.

Drug coated balloon catheters prepared in Example 2 were inserted intothe left ureter and urethra of a female pig. The 4 mm diameter balloonswere inflated to atmospheres in the ureters and the 8 mm balloons wereinflated to 12 atmospheres in the urethra. The balloons were inflated atthe treatment sites for 10 min to release drug and additive, thendeflated and withdraw from the pigs. The inflated overstretch ratio (theratio of inflated balloon diameter to ureter diameter) for the 4 mmdiameter balloons was 1 to 1.5. The overstretch ratio (the ratio ofballoon diameter to urethra diameter) for the 8 mm diameter balloons was2.0 to 2.5. The drug concentration in the urethra and prostate tissuesof the sacrificed animal was measured after 4 hrs. The residual drugremaining on the balloon after use was analyzed.

Example 4. Preclinical Study 1 & 2 Tissue and Balloon Residual DrugContent

The dog tissue drug concentration from the prostatic urethra sample inExample 3, using Formulation 4a, was 0.4 μg/g at 4 hours. The dog tissuedrug concentration from the prostate sample in Example 3, usingFormulation 4a, was 0.367 μg/g at 4 hours. The dog tissue drugconcentration from the pelvic urethra samples in Example 3, usingFormulation 4b, was 11.7 μg/g at 4 hours. The dog tissue drugconcentration from the bulbar urethra samples in Example 3, usingFormulation 4a, was 25.2 μg/g at 4 hours. The dog tissue drugconcentration from the prostatic urethra sample in Example 3, usingFormulation 4a, was 0.586 μg/g at 1 day. The dog tissue drugconcentration from the prostate sample in Example 3, using Formulation4a, was 0.429 μg/g at 1 day. The dog tissue drug concentration from thepelvic urethra samples in Example 3, using Formulation 4b, was 26.6 μg/gat day 1. The dog tissue drug concentration from the distal urethrasamples in Example 3, using Formulation 4a, was 2.04 μg/g at day 1. Theresidual balloon content as a percent of the original drug loading fromthe samples in Example 3, using Formulation 4a, ranged from 45-87%.

The residual balloon content as a percent of the original drug loadingfrom the samples in Example 3, using formulation 4b, ranged from 83-85%.

At 4 hours the proximal (Formulation 4b) right ureter pig tissue drugconcentration from the samples in Example 3 was 17.3 μg/g. At 4 hoursthe female pig urethra (Formulation 4a) drug concentration was 66.9μg/g. The residual balloon content as a percent of the original drugloading from the samples in Example 3 ranged from 6-58%. The averageresidual balloon content for Formulation 4a was 52.8%. The averageresidual balloon content for Formulation 4b was 64.7%.

Example 5. Preclinical Study 3 Sample Preparation

Twenty-three balloon catheters (twelve 8 mm in diameter and 40 mm inlength, six 10 mm in diameter and 40 mm in length, four 12 mm indiameter and 30 mm in length, and three 10 mm in diameter and 30 mm inlength) were inflated to 50% of their nominal inflation pressure andwiped with an ethanol wipe to clean the balloon surface. Next theballoons were coated using various formulations (1-6) in Example 1 withsufficient coating solution to achieve 2 microgram paclitaxel per squaremm of balloon surface. The balloons were then dried, folded, sheathed,packaged in a Tyvek pouch and ethylene oxide sterilized in preparationfor animal testing.

Example 6. Preclinical Study 3 Treatments

For this study male dogs were used. Baseline retrograde urethrogramswere taken to measure the inner diameter of the urethra treatment sitesbefore drug coated balloon treatment. Drug coated balloon cathetersprepared in Example 5 were used with nonoverlapping treatments in theprostatic, pelvic, bulbar, and distal urethra just proximal of the ospenis. The os penis urethra was not treated. The treatment sitediameters were approximately 2.1-8.5 mm. The balloon catheters werechosen such that the nominal overstretch ratio (the ratio of balloondiameter at nominal inflation pressure to urethra diameter) for theprostatic urethra balloons was planned to be approximately 1.7-3.4. Forthe anterior urethra, balloon catheters were chosen such that thenominal overstretch ratio was approximately 1.8-2.3. Prior to insertingthe catheter approximately 5 mL of saline was used to flush the urethra.The 12 mm diameter balloons were inflated in the prostatic urethra andthe 8 and 10 mm diameter balloons were inflated in the anterior urethra.The 12 mm diameter balloons were inflated to 9 atmospheres at thetreatment sites for 10 min to release drug and additive, then deflatedand withdraw from the dogs. The 8 mm diameter balloons were inflated to10 atmospheres at the treatment sites for 10 min to release drug andadditive, then deflated and withdraw from the dogs. The overstretchratio (the ratio of balloon diameter to urethra diameter) for the 12 mmdiameter balloons was 2.0 to 3.0. The overstretch ratio for the 8 and 10mm diameter balloons was 1.3 to 4.0. The amount of drug in the treatedurethra tissues of the sacrificed animal was measured after 1 and 7 daysand the residual drug remaining on the balloon after use was analyzed.

Example 7. Preclinical Study 3 Tissue and Balloon Residual Drug Content

The dog tissue drug concentration from the samples in Example 6 rangedfrom 4-176 μg/g at 1 day and 0.003-23 μg/g at 7 days. The residualballoon content as a percent of the original drug loading from thesamples in Example 6 ranged from 5-98%.

Example 8. Preclinical Study 4 Sample Preparation

One hundred eight balloon catheters (forty-two 8 mm in diameter and 20mm in length, twenty-seven 10 mm in diameter and 40 mm in length,twenty-five 12 mm in diameter and 40 mm in length, five 8 mm in diameterand 55 mm in length, nine 12 mm in diameter and 55 mm in length) wereinflated to 50% of their nominal inflation pressure and wiped with anethanol wipe to clean the balloon surface. Next the balloons were splitinto two groups; one group was coated using Formulation 1 andFormulation 4 from Example 1 with sufficient coating solution to achieve2 microgram paclitaxel per square mm of balloon surface, and the othergroup was coated using the same formulations from Example 1 withsufficient coating solution to achieve 4 microgram paclitaxel per squaremm of balloon surface. The balloons were then dried, folded, sheathed,packaged in a Tyvek pouch and ethylene oxide sterilized in preparationfor animal testing.

Example 9. Preclinical Study 4 Treatments

For this study male dogs were used. Baseline retrograde urethrogramswere taken to measure the inner diameter of the urethra treatment sitesbefore drug coated balloon treatment. Drug coated balloon cathetersprepared in Example 8 were used with nonoverlapping treatments in theprostatic, pelvic, bulbar, and distal urethra just proximal of the ospenis. The os penis urethra was not treated. The treatment sitediameters were approximately 2.6-7.7 mm. The balloon catheters werechosen such that the nominal overstretch ratio (the ratio of balloondiameter at nominal inflation pressure to urethra diameter) for theprostatic urethra balloons was planned to be approximately 2-4. For theanterior urethra, balloon catheters were chosen such that the nominaloverstretch ratio was approximately 1.8-2.3. Prior to inserting thecatheter approximately 5 mL of saline was used to flush the urethra. 8and 12 mm diameter balloons were inflated in the prostatic urethra and 8mm diameter balloons were inflated in the anterior urethra. Theprostatic urethra balloons were inflated to 6-9 atmospheres at thetreatment sites for 10 min to release drug and additive, then deflatedand withdraw from the dogs. The 8 mm diameter balloons were inflated to10 atmospheres at the treatment sites for 10 min to release drug andadditive, then deflated and withdraw from the dogs. The overstretchratio (the ratio of balloon diameter to urethra diameter) for theprostatic urethra balloons was 2.0 to 5.1. The overstretch ratio for theanterior urethra balloons was 1.4 to 2.6. The urethra diameter and theamount of drug in the treated urethra tissues of the sacrificed animalwas measured after 1, 7 and 28 days and the residual drug remaining onthe balloon after use was analyzed. At 28 days samples were taken forhistological evaluation to compare drug coated balloon tissue to plainold balloon and untreated tissue.

Example 10. Preclinical Study 4 Pharmacokinetics, Balloon Residual DrugContent, and Urethra Lumen Gain

The dog tissue average drug concentration from the samples in Example 9was 582 μg/g at 1 day, 0.347 μg/g at day 7, and 4 μg/g at day 28. Thedog tissue average drug concentration from the 2 μg/g and 4 μg/g dosedensity Formulation 1 samples in Example 9 was 20.34 μg/g and 0.73 μg/g,respectively, at day 28. The dog tissue average drug concentration fromthe 2 μg/g and 4 μg/g dose density Formulation 4 samples in Example 9was 0.01 μg/g and 1.20 μg/g, respectively, at day 28. The residualballoon content as a percent of the original drug loading from thesamples in Example 9 ranged from 0-60%. The average residual ballooncontent as a percent of the original drug loading from the 2 μg/g and 4μg/g dose density Formulation 1 samples was 11.5% and 2.4%,respectively. The average residual balloon content as a percent of theoriginal drug loading from the 2 μg/g and 4 μg/g dose densityFormulation 4 samples was 12.2% and 19.9%, respectively. The meanurethral gain at 28 days, treatment site urethra diameter at 28 daysminus the urethral diameter at time of treatment, ranged from 1.6 mm toa lumen loss of 4.4 mm. Examination of the histology samples showed nodiscernable difference between the drug coated balloon treatments, plainballoon treatments, and untreated tissue.

Example 11. Preclinical Study 5 Sample Preparation

Forty balloon catheters (twenty 6 mm in diameter and 20 mm in length,twenty 8 mm in diameter and 20 mm in length) were inflated to 50% oftheir nominal inflation pressure and wiped with an ethanol wipe to cleanthe balloon surface. Next the balloons were split into two groups; onegroup was coated using various formulations (1-6) in Example 1 withsufficient coating solution to achieve 3.5 microgram paclitaxel persquare mm of balloon surface the other group was coated using variousformulations (1-6) in Example 1 with sufficient coating solution toachieve 10 microgram paclitaxel per square mm of balloon surface. Theballoons were then dried, folded, sheathed, packaged in a Tyvek pouchand ethylene oxide sterilized in preparation for animal testing.

Example 12. Preclinical Study 5 Treatments

For this study female pigs were used to allow for easier access to theureters. Before drug coated balloon treatments baseline uretergrams andurethrograms were taken to measure the inner diameters of the ureter andurethra treatment sites before treatment. The treatment site diameterswere approximately 4.0-6.0 mm. The balloon catheters were chosen suchthat the nominal overstretch ratio (the ratio of balloon diameter atnominal inflation pressure to urethra diameter) for the ureter balloonswas planned to be approximately 1.2-1.7. For the urethra, ballooncatheters were chosen such that the nominal overstretch ratio wasapproximately 1.8-2.3. Drug coated balloon catheters prepared in Example11 were used for nonoverlapping treatments. A controlled experiment wasconducted to investigate two procedure parameters; balloon to urethraoverstretch, inflation time, and one product design feature; the drugdose density. The amount of drug in the treated urethra tissues of thesacrificed animal was measured after 1 day and the residual drugremaining on the balloon after use was analyzed.

Example 13. Preclinical Study 5 Balloon Residual Drug Content and TissueDrug Content

The pig tissue average drug concentration from the samples in Example 12was 12.5 μg/g at 1 day. The residual balloon content as a percent of theoriginal drug loading from the samples in Example 12 ranged from 1-52%.

Example 14. Preclinical Study 6 Sample Preparation

Eighty seven balloon catheters (thirty-seven 12 mm in diameter and 20 mmin length, fifty 8 mm in diameter and 20 mm in length) were inflated to50% of their nominal inflation pressure and wiped with an ethanol wipeto clean the balloon surface. Next the balloons were split into twogroups; one group was coated using various formulations (1-6) in Example1 with sufficient coating solution to achieve 3.5 microgram paclitaxelper square mm of balloon surface the other group was coated usingvarious formulations (1-6) in Example 1 with sufficient coating solutionto achieve 10 microgram paclitaxel per square mm of balloon surface. Theballoons were then dried, folded, sheathed, packaged in a Tyvek pouchand ethylene oxide sterilized in preparation for animal testing.

Example 15. Preclinical Study 6 Treatments

For this study casted male pigs were used. Before drug coated balloontreatments baseline urethrograms were taken to measure the innerdiameter of the urethra treatment sites before treatment. Drug coatedballoon catheters prepared in Example 14 were used with nonoverlappingtreatments. Prior to inflation 5-10 mL of saline was used to flush theurethra. A controlled experiment was conducted to investigate the effectof double inflation and drug dose density on the amount of drug in thetreated urethra tissues. The tissue drug content was measured after 1day and 28 days and the residual drug remaining on the balloon after usewas analyzed. Histology samples were taken at 28 days to compare the twodifferent drug dose density catheter groups

Example 16. Preclinical Study 5 Balloon Residual Drug Content and TissueDrug Content

The pig tissue average drug concentration from the samples in Example 14was 83 ng/g at 1 day and 2.5 ng/g at 28 days. The residual ballooncontent as a percent of the original drug loading from the samples inExample 14 ranged from 19-73%.

Example 17. Preclinical Study 7 Sample Preparation

Fifty seven balloon catheters (forty-three 8 mm in diameter and 20 mm inlength, fourteen 20 mm in diameter and 60 mm in length) were inflated to50% of their nominal inflation pressure and wiped with an ethanol wipeto clean the balloon surface. The balloons were coated using variousformulations (1-6) in Example 1 with sufficient coating solution toachieve 3.5 microgram paclitaxel per square mm of balloon surface. Theballoons were then dried, folded, sheathed, packaged in a Tyvek pouchand ethylene oxide sterilized in preparation for animal testing.

Example 18. Preclinical Study 7 Treatments

For this study male dogs were used. These treatments were conductedunder direct visualization using a 2.4 mm outer diameter endoscope. Theendoscope utilized constant saline irrigation to flush visualobstructions away from the field of view, thus the treatment zones wereconstantly being flushed at all times. The first step in the treatmentwas to use cutting balloons (balloon catheters that have blades runninglongitudinally along the length of the balloon) in the prostaticurethra, middle urethra, and distal urethra. Next, uncoated balloonswere used to dilate the treatment locations where the cutting balloonswere used. Then baseline urethrograms were taken to measure the innerdiameter of the urethra treatment sites before drug coated balloontreatment. Finally drug coated balloon catheters prepared in Example 17and uncoated balloon catheters (as controls) were used. The 20 mmdiameter balloons were used in the prostatic urethra and the 8 mmdiameter balloons were used in the anterior urethra. The prostaticurethra balloons were inflated to 4-5 atmospheres at the treatment sitesfor 2 min to release drug and additive, then deflated and withdraw fromthe dogs. The 8 mm diameter balloons were inflated to 10 atmospheres atthe treatment sites for 2 min to release drug and additive, thendeflated and withdraw from the dogs. The overstretch ratio (the ratio ofballoon diameter to urethra diameter) for the prostatic urethra balloonswas 2.9 to 9.7. The overstretch ratio for the anterior urethra balloonswas 1.3 to 3.8. The tissue drug content was measured after 3 day, 7days, and 28 days and the residual drug remaining on the balloon afteruse was analyzed. Histology samples were taken at 3 and 28 days tocompare direct drug coated balloon treatment to cutting balloonpretreatment followed by drug coated balloon treatment.

Example 19. Preclinical Study 7 Pharmacokinetics, Balloon Residual DrugContent, Lumen Gain, and Histology

The dog tissue average drug concentration from the samples in Examplewas 100 μg/g at day 3 and 62 μg/g at day 7 and 33 μg/g at day 28. Theresidual balloon content as a percent of the original drug loading fromthe samples in Example 18 ranged from 2-50%.

Example 20. Preclinical Study 8 Sample Preparation

Thirty nine balloon catheters (8 mm in diameter and 30 mm in length)were inflated to 3 atmospheres and wiped with an ethanol wipe to cleanthe balloon surface. The balloons were coated using Formulations 18, 19,and 23 from Example 1 with sufficient coating solution to achieve 2.5microgram paclitaxel per square mm of balloon surface. The balloons werethen dried, folded, sheathed, packaged in a Tyvek pouch and ethyleneoxide sterilized in preparation for animal testing.

Example 21. Preclinical Study 8 Treatments

For this study male dogs were used. Baseline urethrograms were taken tomeasure the inner diameter of the urethra treatment sites before drugcoated balloon treatment. The treatment site diameters wereapproximately 3.5-4.5 mm. The balloon catheters were chosen such thatthe nominal overstretch ratio (the ratio of balloon diameter at nominalinflation pressure to urethra diameter) for the anterior urethraballoons was approximately 1.8-2.3. Drug coated balloon cathetersprepared in Example were used with nonoverlapping treatments in thepelvic, bulbar, and distal urethra just proximal of the os penis. The ospenis urethra was not treated. Prior to inserting the catheterapproximately 5 mL of saline was used to flush the urethra. The 8 mmdiameter balloons were inflated to 12 atmospheres at the treatment sitesfor 2 min to release drug and additive, then deflated and withdraw fromthe dogs. The inflated overstretch ratio (the ratio of inflated balloondiameter to urethra diameter) for the anterior urethra balloons wasapproximately 2.0-2.5. The tissue drug content was measured after 1 dayand the residual drug remaining on the balloon after use was analyzed.

Example 22. Preclinical Study 8 Tissue Drug Content and Balloon ResidualDrug Content

The dog tissue drug concentration from the pelvic urethra samples inExample 21 was 0.305, 1.17, 17.3, 33.4 μg/g at day 1. The dog tissuedrug concentration from the bulbar urethra samples in Example 21 was0.28, 4.31, 44.5, 57.8 μg/g at day 1. The dog tissue drug concentrationfrom the distal urethra samples in Example 21 was 7.37, 38.9, 238, 268μg/g at day 1. The average drug concentration from Formulations 18, 19,and 23 was 6.5, 33.6, and 137.7 μg/g, respectively, at day 1. Theresidual balloon content as a percent of the original drug loading fromthe samples in Example 21 ranged from 20.4-81.7%. The average residualballoon content as a percentage of the original drug loading fromFormulations 18, 19, and 23 was 57.7%, 68.7%, and 51.9%, respectively.

Example 23. Bench-Top Drug Release Testing Sample Preparation

Forty nine balloon catheters (thirty-one 8 mm in diameter and 30 mm inlength, six 10 mm in diameter and 20 mm in length, thirteen 12 mm indiameter and 20 mm in length) were inflated to 3 atmospheres and wipedwith an ethanol wipe to clean the balloon surface. The balloons werecoated using various formulations (1-34) in Example 1 with sufficientcoating solution to achieve either 2.5 or 3.5 microgram paclitaxel persquare mm of balloon surface. The balloons were then dried, folded,sheathed, packaged in a Tyvek pouch and ethylene oxide sterilized inpreparation for bench testing.

Example 24. Bench-Top Drug Release Testing

A bench top drug release apparatus was developed that consisted of a 10inch long by 2 inch diameter cylindrical vessel placed inside atemperature controlled water bath. The cylindrical vessel was filledwith 0.9% saline and maintained at 37° C. for the testing. An 8 French(i.e., wherein 3 French is 1 mm) by 13 cm long introducer sheathpenetrated the top of the cylindrical vessel and was used as a conduitto pass balloon catheter samples into the cylindrical vessel. Thesamples developed in Example were individually passed into thecylindrical vessel where they soaked for 1 minute prior to beinginflated to 10 atmospheres for 1 minute and then withdrawn. Theremaining drug on the balloon was analyzed to determine how much drugwas released. The amount of drug released during this testing rangedfrom 37% to 97%.

Additional Embodiments

The following exemplary embodiments are provided, the numbering of whichis not to be construed as designating levels of importance:

Embodiment 1 provides a balloon catheter for delivering a therapeuticagent to a target site of a nonvascular body lumen, the balloon cathetercomprising:

a coating layer overlying an exterior surface of a balloon, wherein thecoating layer comprises one or more water-soluble additives, and aninitial drug load of a hydrophobic therapeutic agent;

wherein

the hydrophobic therapeutic agent is selected from the group consistingof paclitaxel, paclitaxel analogues, rapamycin, rapamycin analogues, andcombinations thereof,

the water-soluble additive is chosen from N-acetylglucosamine,N-octyl-D-gluconamide, N-nonanoyl-N-methylglycamine, N-octanoyl-N-methylglutamine, C6-ceramide, dihydro-C6-ceramide, cerabroside, sphingomyelin,galaclocerebrosides, lactocerebrosides, N-acetyl-D-sphingosine,N-hexanoyl-D-sphingosine, N-octonoyl-D-sphingosine,N-lauroyl-D-sphingosine, N-palmitoyl-D-sphingosine,N-oleoyl-D-sphingosine, PEG caprylic/capric diglycerides, PEG8caprylic/capric glycerides, PEG caprylate, PEG8 caprylate, PEG caprate,PEG caproate, glyceryl monocaprylate, glyceryl monocaprate, glycerylmonocaproate, monolaurin, monocaprin, monocaprylin, monomyristin,monopalmitolein, monoolein, creatine, creatinine, agmatine, citrulline,guanidine, sucralose, aspartame, hypoxanthine, theobromine,theophylline, adenine, uracil, uridine, guanine, thymine, thymidine,xanthine, xanthosine, xanthosine monophosphate, caffeine, allantoin,(2-hydroxyethyl)urea, N,N′-bis(hydroxymethyl)urea, pentaerythritolethoxylate, pentaerythritol propoxylate, pentaerythritolpropoxylate/ethoxylate, glycerol ethoxylate, glycerol propoxylate,trimethylolpropane ethoxylate, pentaerythritol, dipentaerythritol, crownether, 18-crown-6, 15-crown-5, 12-crown-4, and combinations thereof.

Embodiment 2 provides the balloon catheter of Embodiment 1, wherein theone or more water-soluble additives promote a rapid release of thehydrophobic therapeutic agent from the balloon, and whereby the rapidrelease comprises a residual drug amount of the hydrophobic therapeuticagent remaining on the balloon after the balloon is inflated at thetarget site of the nonvascular body lumen for an inflation period offrom about 0.1 minutes to about 10 minutes and subsequently removed fromthe nonvascular lumen.

Embodiment 3 provides the balloon catheter of Embodiment 2, wherein theresidual drug amount is about 70% or less of the initial drug load.

Embodiment 4 provides the balloon catheter of any one of Embodiments1-3, wherein the initial drug load is from about 1 microgram to about 20micrograms of the hydrophobic therapeutic agent per square millimeter ofthe balloon.

Embodiment 5 provides the balloon catheter of any one of Embodiments1-4, wherein the initial drug load is from about 2 to about 6 microgramsof the hydrophobic therapeutic agent per square millimeter of theballoon.

Embodiment 6 provides the balloon catheter of any one of Embodiments1-5, wherein the nonvascular body lumen is one of esophagus, airways,sinus, trachea, colon, biliary tract, urinary tract, prostate, urethral,ureteral, and other nonvascular lumens.

Embodiment 7 provides the balloon catheter of any one of Embodiments1-6, wherein the ratio by weight of the hydrophobic therapeutic agent inthe coating layer to the total weight of the one or more water-solubleadditives in the coating layer is from about 0.05 to about 20.

Embodiment 8 provides the balloon catheter of any one of Embodiments1-7, wherein the ratio by weight of the hydrophobic therapeutic agent inthe coating layer to the total weight of the one or more water-solubleadditives in the coating layer is from about 2 to about 6.

Embodiment 9 provides the balloon catheter of any one of Embodiments1-8, wherein the balloon catheter has a ratio of an inflated balloondiameter at one or more pressures equal to or greater than 3 atm (304kPa) atm and equal to or less than 30 atm (3040 kPa) to the nonvascularbody lumen diameter of about 1.01 to about 30.

Embodiment 10 provides the balloon catheter of any one of Embodiments1-9, wherein the balloon catheter has a ratio of an inflated balloondiameter at about 6 atm (608 kPa) to the nonvascular body lumen diameterof about 1.01 to about 30.

Embodiment 11 provides the balloon catheter of any one of Embodiments1-10, wherein the balloon catheter has a ratio of a nominal inflatedballoon diameter to the undilated nonvascular body lumen diameter ofabout 1.01 to about 30.

Embodiment 12 provides the balloon catheter of any one of Embodiments1-11, wherein the balloon catheter is for delivering the therapeuticagent to the target site of the nonvascular body lumen after thenonvascular body lumen has been flushed with water, saline solution, ora water solution comprising at least one water soluble additive.

Embodiment 13 provides a method for treating a stricture in anonvascular body lumen, the method comprising:

flushing the nonvascular body lumen with water, saline solution, or awater solution comprising at least one water soluble additive;

inserting a balloon catheter to a target site in the stricture in thenonvascular body lumen having a diameter, the balloon cathetercomprising a balloon and a coating layer overlying external surfaces ofthe balloon, wherein

the coating layer comprises one or more water-soluble additives and aninitial drug load of a hydrophobic therapeutic agent,

the hydrophobic therapeutic agent is selected from the group consistingof paclitaxel, paclitaxel analogues, rapamycin, rapamycin analogues, andcombinations thereof,

the water-soluble additive is chosen from N-acetylglucosamine,N-octyl-D-gluconamide, N-Nonanoyl-N-methylglycamine, N-octanoyl-N-methylglutamine C6-ceramide, dihydro-C6-ceramide, cerabroside, sphingomyelin,galaclocerebrosides, lactocerebrosides, N-acetyl-D-sphingosine,N-hexanoyl-D-sphingosine, N-octonoyl-D-sphingosine,N-Lauroyl-D-sphingosine, N-palmitoyl-D-sphingosine,N-oleoyl-D-sphingosine, PEG caprylic/capric diglycerides, PEG8caprylic/capric glycerides, PEG caprylate, PEG8 caprylate, PEG caprate,PEG caproate, glyceryl monocaprylate, glyceryl monocaprate, glycerylmonocaproate, monolaurin, monocaprin, monocaprylin, monomyristin,monopalmitolein, monoolein, creatine, creatinine, agmatine, citrulline,guanidine, sucralose, aspartame, hypoxanthine, theobromine,theophylline, adenine, uracil, uridine, guanine, thymine, thymidine,xanthine, xanthosine, xanthosine monophosphate, caffeine, allantoin,(2-hydroxyethyl)urea, N,N′-bis(hydroxymethyl)urea, pentaerythritolethoxylate, pentaerythritol propoxylate, pentaerythritolpropoxylate/ethoxylate, glycerol ethoxylate, glycerol propoxylate,trimethylolpropane ethoxylate, pentaerythritol, dipentaerythritol, crownether, 18-crown-6, 15-crown-5, 12-crown-4, and combinations thereof;

inflating the balloon until the coating layer contacts walls of thestricture in the nonvascular body lumen at the target site for aninflation period, wherein the ratio of the inflated balloon diameter tothe nonvascular body lumen diameter is about 1.01 to about 30;

deflating the balloon after the inflation period, wherein the inflationperiod is from about 0.1 minutes to about 10 minutes; and

withdrawing the balloon catheter from the stricture in the nonvascularbody lumen.

Embodiment 14 provides the method of Embodiment 13, wherein the one ormore water-soluble additives promote rapid release of the hydrophobictherapeutic agent from the balloon at the target site during aninflation period.

Embodiment 15 provides the method of any one of Embodiments 13-14,wherein the balloon has thereon a residual drug amount after thewithdrawing.

Embodiment 16 provides the method of any one of Embodiments 13-15,wherein the stricture in the nonvascular body lumen is one of urethralstrictures, benign prostatic hyperplasia (BPH) strictures, ureteralstrictures, esophageal strictures, sinus strictures, and biliary tractstrictures.

Embodiment 17 provides the method of any one of Embodiments 13-16,wherein the ratio by weight of the therapeutic agent in the coatinglayer to the total weight of the one or more water-soluble additives inthe coating layer is from about 0.05 to about 20.

Embodiment 18 provides the method of any one of Embodiments 13-17,wherein the ratio by weight of the hydrophobic therapeutic agent in thecoating layer to the total weight of the one or more water-solubleadditives in the coating layer is from about 2 to about 6.

Embodiment 19 provides the method of any one of Embodiments 13-18,wherein the initial drug load is from about 1 microgram to about 20micrograms of the hydrophobic therapeutic agent per square millimeter ofthe balloon.

Embodiment 20 provides the method of any one of Embodiments 13-19,wherein the initial drug load is from about 1 to about 6 micrograms ofthe hydrophobic therapeutic agent per square millimeter of the balloon.

Embodiment 21 provides the method of any one of Embodiments 13-20,wherein the balloon has thereon a residual drug amount of less thanabout 70% of the initial drug load after the withdrawing.

Embodiment 22 provides the method of any one of Embodiments 13-21,wherein the balloon catheter has a ratio of an inflated balloon diameterat one or more pressures equal to or greater than 3 atm (304 kPa) atmand equal to or less than 30 atm (3040 kPa) to the undilated nonvascularbody lumen diameter of about 1.01 to about 30.

Embodiment 23 provides the method of any one of Embodiments 13-22,wherein the balloon catheter has a ratio of an inflated balloon diameterat about 6 atm (608 kPa) to the undilated nonvascular body lumendiameter of about 1.01 to about 30.

Embodiment 24 provides the balloon catheter of any one of Embodiments13-23, wherein the balloon catheter has a ratio of a nominal inflatedballoon diameter to the undilated nonvascular body lumen diameter ofabout 1.01 to about 30.

Embodiment 25 provides a method for treating at least one of benignprostatic hyperplasia and prostate cancer, the method comprising:

flushing a prostate with water, saline solution, or a water solutioncomprising at least one water soluble additive;

inserting a balloon catheter to a target site in the prostate, theballoon catheter comprising a balloon and a coating layer overlyingexternal surfaces of the balloon, wherein the coating layer comprisesone or more water-soluble additives and an initial drug load of ahydrophobic therapeutic agent, wherein

the hydrophobic therapeutic agent is selected from the group consistingof paclitaxel, paclitaxel analogues, rapamycin, rapamycin analogues, andcombinations thereof,

the water-soluble additive is chosen from N-acetylglucosamine,N-octyl-D-gluconamide, N-nonanoyl-N-methylglycamine, N-octanoyl-N-methylglutamine, C6-ceramide, dihydro-C6-ceramide, cerabroside, sphingomyelin,galaclocerebrosides, lactocerebrosides, N-acetyl-D-sphingosine,N-hexanoyl-D-sphingosine, N-octonoyl-D-sphingosine,N-lauroyl-D-sphingosine, N-palmitoyl-D-sphingosine,N-oleoyl-D-sphingosine, PEG caprylic/capric diglycerides, PEG8caprylic/capric glycerides, PEG caprylate, PEG8 caprylate, PEG caprate,PEG caproate, glyceryl monocaprylate, glyceryl monocaprate, glycerylmonocaproate, monolaurin, monocaprin, monocaprylin, monomyristin,monopalmitolein, monoolein, creatine, creatinine, agmatine, citrulline,guanidine, sucralose, aspartame, hypoxanthine, theobromine,theophylline, adenine, uracil, uridine, guanine, thymine, thymidine,xanthine, xanthosine, xanthosine monophosphate, caffeine, allantoin,(2-hydroxyethyl)urea, N,N′-bis(hydroxymethyl)urea, pentaerythritolethoxylate, pentaerythritol propoxylate, pentaerythritolpropoxylate/ethoxylate, glycerol ethoxylate, glycerol propoxylate,trimethylolpropane ethoxylate, pentaerythritol, dipentaerythritol, crownether, 18-crown-6, 15-crown-5, 12-crown-4, and combinations thereof,

inflating the balloon until the coating layer contacts walls of thebenign prostatic hyperplasia or the prostate cancer at the target sitefor an inflation period:

deflating the balloon after the inflation period, wherein the inflationperiod is from about 0.1 minutes to about 10 minutes; and

withdrawing the balloon catheter from the prostate.

Embodiment 26 provides the method of Embodiment 25, wherein the one ormore water-soluble additives promote rapid release of the hydrophobictherapeutic agent from the balloon at the target site during aninflation period.

Embodiment 27 provides the method of any one of Embodiments 25-26,wherein the balloon has thereon a residual drug amount after thewithdrawing.

Embodiment 28 provides the method of any one of Embodiments 25-27,wherein the ratio by weight of the therapeutic agent in the coatinglayer to the total weight of the one or more water-soluble additives inthe coating layer is from about 0.05 to about 20.

Embodiment 29 provides the method of any one of Embodiments 25-28,wherein the ratio by weight of the therapeutic agent in the coatinglayer to the total weight of the one or more water-soluble additives inthe coating layer is from about 2 to about 6.

Embodiment 30 provides the method of any one of Embodiments 25-29,wherein the initial drug load is from about 1 to about 20 micrograms ofthe hydrophobic therapeutic agent per square millimeter of the balloon.

Embodiment 31 provides the method of any one of Embodiments 25-30,wherein the initial drug load is from about 1 to about 6 micrograms ofthe hydrophobic therapeutic agent per square millimeter of the balloon;and the residual drug amount is about 70% or less of the initial drugload.

Embodiment 32 provides the method of any one of Embodiments 25-31,wherein during the inflating the balloon catheter has a ratio ofinflated balloon diameter to the undilated diameter of the benignprostatic hyperplasia or the prostate cancer at the target site of about1.01 to about 30.

Embodiment 33 provides the method of any one of Embodiments 25-32,wherein the balloon catheter has a ratio of an inflated balloon diameterat one or more pressures equal to or greater than 3 atm (304 kPa) atmand equal to or less than 30 atm (3040 kPa) to the undilated diameter ofthe benign prostatic hyperplasia or the prostate cancer at the targetsite of about 1.01 to about 30.

Embodiment 34 provides the method of any one of Embodiments 25-33,wherein the balloon catheter has a ratio of an inflated balloon diameterat about 6 atm (608 kPa) to the undilated diameter of the benignprostatic hyperplasia or the prostate cancer at the target site of about1.01 to about 30.

Embodiment 35 provides the method of any one of Embodiments 25-34,wherein the balloon catheter has a ratio of a nominal inflated balloondiameter to the undilated diameter of the benign prostatic hyperplasiaor the prostate cancer at the target site of about 1.01 to about 30.

Embodiment 36 provides a method for treating a urethral stricture, themethod comprising:

flushing the urethral stricture with water, saline solution, or a watersolution comprising at least one water soluble additive;

inserting a balloon catheter to a target site in the urethral stricture,the balloon catheter comprising a balloon and a coating layer overlyingexternal surfaces of the balloon, wherein

the coating layer comprises one or more water-soluble additives and aninitial drug load of a hydrophobic therapeutic agent,

the hydrophobic therapeutic agent is selected from the group consistingof paclitaxel, paclitaxel analogues, rapamycin, rapamycin analogues, andcombinations thereof,

the water-soluble additive is chosen from N-acetylglucosamine,N-octyl-D-gluconamide, N-nonanoyl-N-methylglycamine, N-octanoyl-N-methylglutamine, C6-ceramide, dihydro-C6-ceramide, cerabroside, sphingomyelin,galaclocerebrosides, lactocerebrosides, N-acetyl-D-sphingosine,N-hexanoyl-D-sphingosine, N-octonoyl-D-sphingosine,N-lauroyl-D-sphingosine, N-palmitoyl-D-sphingosine,N-oleoyl-D-sphingosine, PEG caprylic/capric diglycerides, PEG8caprylic/capric glycerides, PEG caprylate, PEG8 caprylate, PEG caprate,PEG caproate, glyceryl monocaprylate, glyceryl monocaprate, glycerylmonocaproate, monolaurin, monocaprin, monocaprylin, monomyristin,monopalmitolein, monoolein, creatine, creatinine, agmatine, citrulline,guanidine, sucralose, aspartame, hypoxanthine, theobromine,theophylline, adenine, uracil, uridine, guanine, thymine, thymidine,xanthine, xanthosine, xanthosine monophosphate, caffeine, allantoin,(2-hydroxyethyl)urea, N,N′-bis(hydroxymethyl)urea, pentaerythritolethoxylate, pentaerythritol propoxylate, pentaerythritolpropoxylate/ethoxylate, glycerol ethoxylate, glycerol propoxylate,trimethylolpropane ethoxylate, pentaerythritol, dipentaerythritol, crownether, 18-crown-6, 15-crown-5, 12-crown-4, and combinations thereof, and

the ratio by weight of the hydrophobic therapeutic agent in the coatinglayer to the total weight of the one or more water-soluble additives inthe coating layer is from about 0.05 to about 20;

inflating the balloon until the coating layer contacts walls of theurethral stricture at the target site for an inflation period;

deflating the balloon after the inflation period, wherein the inflationperiod is from about 0.1 minutes to about 10 minutes; and

withdrawing the balloon catheter from the urethral stricture.

Embodiment 37 provides the method of Embodiment 36, wherein the one ormore water-soluble additives promote rapid release of the hydrophobictherapeutic agent from the balloon at the target site during aninflation period.

Embodiment 38 provides the method of any one of Embodiments 36-37,wherein the balloon has thereon a residual drug amount of less thanabout 70% of the initial drug load after the withdrawing.

Embodiment 39 provides the method of any one of Embodiments 36-38,wherein the ratio by weight of the therapeutic agent in the coatinglayer to the total weight of the one or more water-soluble additives inthe coating layer is from about 0.5 to about 8.

Embodiment 40 provides the method of any one of Embodiments 36-39,wherein the ratio by weight of the therapeutic agent in the coatinglayer to the total weight of the one or more water-soluble additives inthe coating layer is from about 2 to about 6.

Embodiment 41 provides the method of any one of Embodiments 36-40,wherein the initial drug load is from about 1 to about 20 micrograms ofthe hydrophobic therapeutic agent per square millimeter of the balloon.

Embodiment 42 provides the method of any one of Embodiments 36-41,wherein the initial drug load is from about 1 to about 6 micrograms ofthe hydrophobic therapeutic agent per square millimeter of the balloon.

Embodiment 43 provides the method of any one of Embodiments 36-42,wherein during the inflating the balloon catheter has a ratio ofinflated balloon diameter to the undilated diameter of the urethralstricture at the target site of about 1.01 to about 30.

Embodiment 44 provides the method of any one of Embodiments 36-43,wherein the balloon catheter has a ratio of an inflated balloon diameterat one or more pressures equal to or greater than 3 atm (304 kPa) atmand equal to or less than 30 atm (3040 kPa) to the undilated diameter ofthe urethral stricture at the target site of about 1.01 to about 30.

Embodiment 45 provides the method of any one of Embodiments 36-44,wherein the balloon catheter has a ratio of an inflated balloon diameterat about 6 atm (608 kPa) to the undilated diameter of the urethralstricture at the target site of about 1.01 to about 30.

Embodiment 46 provides the method of any one of Embodiments 36-45,wherein the balloon catheter has a ratio of a nominal inflated balloondiameter to the undilated diameter of the urethral stricture at thetarget site of about 1.01 to about 30.

Embodiment 47 provides a method for treating an esophageal stricture,the method comprising:

flushing the esophageal stricture with water, saline solution or a watersolution comprising at least one water soluble additive;

inserting a balloon catheter to a target site in the esophagealstricture, the balloon catheter comprising a balloon and a coating layeroverlying external surfaces of the balloon, wherein

the coating layer comprises one or more water-soluble additives and aninitial drug load of a hydrophobic therapeutic agent,

the hydrophobic therapeutic agent is selected from the group consistingof paclitaxel, paclitaxel analogues, rapamycin, rapamycin analogues, andcombinations thereof,

the water-soluble additive is chosen from N-acetylglucosamine,N-octyl-D-gluconamide, N-nonanoyl-N-methylglycamine, N-octanoyl-N-methylglutamine, C6-ceramide, dihydro-C6-ceramide, cerabroside, sphingomyelin,galaclocerebrosides, lactocerebrosides, N-acetyl-D-sphingosine,N-hexanoyl-D-sphingosine, N-octonoyl-D-sphingosine,N-lauroyl-D-sphingosine, N-palmitoyl-D-sphingosine,N-oleoyl-D-sphingosine, PEG caprylic/capric diglycerides, PEG8caprylic/capric glycerides, PEG caprylate, PEG8 caprylate, PEG caprate,PEG caproate, glyceryl monocaprylate, glyceryl monocaprate, glycerylmonocaproate, monolaurin, monocaprin, monocaprylin, monomyristin,monopalmitolein, monoolein, creatine, creatinine, agmatine, citrulline,guanidine, sucralose, aspartame, hypoxanthine, theobromine,theophylline, adenine, uracil, uridine, guanine, thymine, thymidine,xanthine, xanthosine, xanthosine monophosphate, caffeine, allantoin,(2-hydroxyethyl)urea, N,N′-bis(hydroxymethyl)urea, pentaerythritolethoxylate, pentaerythritol propoxylate, pentaerythritolpropoxylate/ethoxylate, glycerol ethoxylate, glycerol propoxylate,trimethylolpropane ethoxylate, pentaerythritol, dipentaerythritol, crownether, 18-crown-6, 15-crown-5, 12-crown-4, and combinations thereof, and

the ratio by weight of the hydrophobic therapeutic agent in the coatinglayer to the total weight of the one or more water-soluble additives inthe coating layer is from about 0.05 to about 20;

inflating the balloon until the coating layer contacts walls of theesophageal stricture at the target site for an inflation period; and

deflating the balloon after the inflation period, wherein the inflationperiod is from about 0.1 minutes to about 10 minutes; and withdrawingthe balloon catheter from the esophageal stricture.

Embodiment 48 provides the method of Embodiment 47, wherein the one ormore water-soluble additives promote rapid release of the hydrophobictherapeutic agent from the balloon at the target site during aninflation period.

Embodiment 49 provides the method of any one of Embodiments 47-48,wherein the balloon has thereon a residual drug amount of less thanabout 70% of the initial drug load after the withdrawing.

Embodiment 50 provides the method of any one of Embodiments 47-49,wherein the ratio by weight of the therapeutic agent in the coatinglayer to the total weight of the one or more water-soluble additives inthe coating layer is from about about 0.5 to about 8.

Embodiment 51 provides the method of any one of Embodiments 47-50,wherein the ratio by weight of the therapeutic agent in the coatinglayer to the total weight of the one or more water-soluble additives inthe coating layer is from about 2 to about 6.

Embodiment 52 provides the method of any one of Embodiments 47-51,wherein the initial drug load is from about 1 to about 20 micrograms ofthe hydrophobic therapeutic agent per square millimeter of the balloon.

Embodiment 53 provides the method of any one of Embodiments 47-52,wherein the initial drug load is from about 1 to about 6 micrograms ofthe hydrophobic therapeutic agent per square millimeter of the balloon.

Embodiment 54 provides the method of any one of Embodiments 47-53,wherein during the inflating the balloon catheter has a ratio ofinflated balloon diameter to the diameter of the esophageal structure atthe target site of about 1.01 to about 30.

Embodiment 55 provides the method of any one of Embodiments 47-54,wherein the balloon catheter has a ratio of an inflated balloon diameterat one or more pressures equal to or greater than 3 atm (304 kPa) atmand equal to or less than 30 atm (3040 kPa) to the undilated diameter ofthe esophageal stricture at the target site of about 1.01 to about 30.

Embodiment 56 provides the method of any one of Embodiments 47-55,wherein the balloon catheter has a ratio of an inflated balloon diameterat about 6 atm (608 kPa) to the undilated diameter of the esophagealstricture at the target site of about 1.01 to about 30.

Embodiment 57 provides the method of any one of Embodiments 47-56,wherein the balloon catheter has a ratio of a nominal inflated balloondiameter to the undilated diameter of the esophageal stricture at thetarget site of about 1.01 to about 30.

Embodiment 58 provides the balloon catheter or method of any one or anycombination of Embodiments 1-57 optionally configured such that allelements or options recited are available to use or select from.

What is claimed is:
 1. A method of treating a gastrointestinal orbiliary tract stricture, the method comprising: providing a soakedballoon catheter in the gastrointestinal or biliary tract stricture, theballoon catheter comprising a balloon and a coating layer overlying anexternal surface of the balloon, the coating layer comprising ahydrophobic therapeutic agent and one or more water-soluble additives;inflating the balloon so that the coating layer contacts walls of thestricture and the therapeutic agent is delivered to the walls of thestricture; deflating the balloon after an inflation period; andwithdrawing the balloon catheter from the stricture.
 2. The method ofclaim 1, wherein the hydrophobic therapeutic agent comprises paclitaxel,a paclitaxel analogue, docetaxel, a docetaxel analogue, taxol, a taxolanalogue, rapamycin, a rapamycin analogue, sirolimus, a sirolimusanalogue, everolimus, an everolimus analogue, tacrolimus, a tacrolimusanalogue, mammalian target of rapamycin (mTOR) inhibitors, an mTORinhibitor analogue, or a combination thereof.
 3. The method of claim 1,further comprising flushing the stricture with a flushing solutioncomprising water or saline, wherein the balloon catheter is soaked inthe flushing solution in the stricture.
 4. The method of claim 1,wherein the balloon catheter is soaked outside the body with a soakingsolution comprising water or saline.
 5. The method of claim 1, whereinthe stricture is a gastrointestinal tract stricture, a stomachstricture, a colon stricture, a small intestine stricture, or anesophageal stricture.
 6. The method of claim 1, wherein the stricture isa biliary tract stricture.
 7. The method of claim 1, wherein thewater-soluble additive is chosen from N-acetylglucosamine,N-octyl-D-gluconamide, N-nonanoyl-N-methylglycamine,N-octanoyl-N-methylglutamine, C6-ceramide, dihydro-C6-ceramide,cerebroside, sphingomyelin, galaclocerebrosides, lactocerebrosides,N-acetyl-D-sphingosine, N-hexanoyl-D-sphingosine, Noctonoyl-D-sphingosine, N-lauroyl-D-sphingosine,N-palmitoyl-D-sphingosine, N-oleoyl-D-sphingosine, PEG caprylic/capricdiglycerides, PEG8 caprylic/capric glycerides, PEG caprylate, PEG8caprylate, PEG caprate, PEG caproate, glyceryl monocaprylate, glycerylmonocaprate, glyceryl monocaproate, monolaurin, monocaprin,monocaprylin, monomyristin, monopalmitolein, monoolein, creatine,creatinine, agmatine, citrulline, guanidine, sucralose, aspartame,hypoxanthine, theobromine, theophylline, adenine, uracil, uridine,guanine, thymine, thymidine, xanthine, xanthosine, xanthosinemonophosphate, caffeine, allantoin, (2-hydroxyethyl)urea,N,N′-bis(hydroxymethyl)urea, pentaerythritol ethoxylate, pentaerythritolpropoxylate, pentaerythritol propoxylate/ethoxylate, glycerolethoxylate, glycerol propoxylate, trimethylolpropane ethoxylate,pentaerythritol, dipentaerythritol, crown ether, 18-crown-6, 15-crown-5,12-crown-4, and combinations thereof.
 8. The method of claim 1, whereinthe water-soluble additive is chosen from pentaerythritol ethoxylate,pentaerythritol propoxylate, and combinations thereof.
 9. A method oftreating a gastrointestinal or biliary tract stricture, the methodcomprising: providing a soaked balloon catheter in the gastrointestinalor biliary tract stricture, the balloon catheter comprising a balloonand a coating layer overlying an external surface of the balloon, thecoating layer comprising a hydrophobic therapeutic agent and one or morewater-soluble additives; inflating the balloon until the coating layercontacts walls of the stricture and delivers the therapeutic agent tothe walls of the stricture; deflating the balloon after an inflationperiod; visualizing with a scope the inflating of the balloon, thecontacting of the coating layer with the walls of the stricture, thedelivery of the therapeutic agent to the walls of the stricture, thedeflating of the balloon, the therapeutic agent on the walls of thestricture after the deflation, or a combination thereof; and withdrawingthe balloon catheter from the stricture.
 10. The method of claim 9,comprising visualizing the therapeutic agent on the walls of thestricture after the deflation with the scope.
 11. The method of claim 9,wherein the hydrophobic therapeutic agent comprises paclitaxel, apaclitaxel analogue, docetaxel, a docetaxel analogue, taxol, a taxolanalogue, rapamycin, a rapamycin analogue, sirolimus, a sirolimusanalogue, everolimus, an everolimus analogue, tacrolimus, a tacrolimusanalogue, mammalian target of rapamycin (mTOR) inhibitors, an mTORinhibitor analogue, or a combination thereof.
 12. The method of claim 9,further comprising flushing the stricture with a flushing solutioncomprising water or saline, wherein the balloon catheter is soaked inthe flushing solution in the stricture.
 13. The method of claim 9,wherein the balloon catheter is soaked outside the body with a soakingsolution comprising water or saline.
 14. The method of claim 9, whereinthe stricture is a gastrointestinal tract stricture, a stomachstricture, a colon stricture, a small intestine stricture, or anesophageal stricture.
 15. The method of claim 9, wherein the strictureis a biliary tract stricture.
 16. The method of claim 9, wherein thewater-soluble additive is chosen from N-acetylglucosamine,N-octyl-D-gluconamide, N-nonanoyl-N-methylglycamine,N-octanoyl-N-methylglutamine, C6-ceramide, dihydro-C6-ceramide,cerebroside, sphingomyelin, galaclocerebrosides, lactocerebrosides,N-acetyl-D-sphingosine, N-hexanoyl-D-sphingosine, Noctonoyl-D-sphingosine, N-lauroyl-D-sphingosine,N-palmitoyl-D-sphingosine, N-oleoyl-D-sphingosine, PEG caprylic/capricdiglycerides, PEG8 caprylic/capric glycerides, PEG caprylate, PEG8caprylate, PEG caprate, PEG caproate, glyceryl monocaprylate, glycerylmonocaprate, glyceryl monocaproate, monolaurin, monocaprin,monocaprylin, monomyristin, monopalmitolein, monoolein, creatine,creatinine, agmatine, citrulline, guanidine, sucralose, aspartame,hypoxanthine, theobromine, theophylline, adenine, uracil, uridine,guanine, thymine, thymidine, xanthine, xanthosine, xanthosinemonophosphate, caffeine, allantoin, (2-hydroxyethyl)urea,N,N′-bis(hydroxymethyl)urea, pentaerythritol ethoxylate, pentaerythritolpropoxylate, pentaerythritol propoxylate/ethoxylate, glycerolethoxylate, glycerol propoxylate, trimethylolpropane ethoxylate,pentaerythritol, dipentaerythritol, crown ether, 18-crown-6, 15-crown-5,12-crown-4, and combinations thereof.
 17. The method of claim 9, whereinthe water-soluble additive is chosen from pentaerythritol ethoxylate,pentaerythritol propoxylate, and combinations thereof.
 18. The method ofclaim 9, further comprising positioning the balloon catheter in thestricture, and visualizing the positioning of the balloon catheter inthe stricture with the scope.
 19. The method of claim 9, wherein thescope and the balloon catheter are positioned side-by-side when theballoon catheter is in the stricture.
 20. The method of claim 9, whereinthe balloon catheter is in the scope when the balloon catheter is in thestricture.
 21. The method of claim 9, wherein the scope comprises anendoscope, enteroscope, colonoscope, sigmoidoscope, rectoscope,anoscope, or a combination thereof.
 22. A method of treating agastrointestinal or biliary tract stricture, the method comprising:providing a soaked balloon catheter in the gastrointestinal or biliarytract stricture, the balloon catheter comprising a balloon and a coatinglayer overlying an external surface of the balloon, the coating layercomprising a hydrophobic therapeutic agent and one or more water-solubleadditives; visualizing the balloon catheter with a scope; inflating theballoon so that the coating layer contacts walls of the stricture andthe therapeutic agent is delivered to the walls of the stricture;deflating the balloon after an inflation period; and withdrawing theballoon catheter from the stricture.